Abstract
The tumor necrosis factor receptor superfamily (TNFRSF) is a pivotal immunoregulatory group of receptors involved in almost all aspects of immunity. Signaling by TNFRSF members has a multifactorial impact on the development and efficacy of anti-cancer immunity and on cancer cells directly. For instance, the role of the TNFRSF in immunity includes the CD40-/CD40L-mediated critical licensing step of dendritic cell-mediated activation of T cells, GITR-/GITRL-mediated development of regulatory T cell function and 4-1BB−/4-1BBL-mediated co-stimulation of cytotoxic T cells after MHC/TCR interaction. Therapeutic activation of signaling by TNFRSF members is a major focus within oncology and cancer immunology with a range of therapeutics being developed to exploit signaling by this family, including monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), and ligand-based targeting approaches. In this chapter, we highlight a select group of TNFRSF members, specifically CD40, 4-1BB, CD27, OX40, and GITR, that have gained prominence in cancer immunotherapy and provide a description of recent insights into biology followed by a review of cutting-edge TNFRSF signaling-based cancer immunotherapeutics.
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References
Aftimos P, Rolfo C, Rottey S, Offner F, Bron D, Maerevoet M, Soria JC, Moshir M, Dreier T, Van Rompaey L, Michot JM, Silence K, Hultberg A, Gandini D, de Haard H, Ribrag V, Peeters M, Thibault A, Leupin N, Awada A (2017) Phase I dose-escalation study of the anti-CD70 antibody ARGX-110 in advanced malignancies. Clin Cancer Res 23(21):6411–6420
Al Sayed MF, Ruckstuhl CA, Hilmenyuk T, Claus C, Bourquin JP, Bornhauser BC, Radpour R, Riether C, Ochsenbein AF (2017) CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies. Blood 130(3):297–309
Alves Costa Silva C, Facchinetti F, Routy B, Derosa L (2020) New pathways in immune stimulation: targeting OX40. ESMO Open 5(1)
Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, Krishnan S, Posada JM, Ghosh M, Mamessier E, Wong C, Ferraro GB, Batista A, Wang N, Badeaux M, Roberge S, Xu L, Huang P, Shalek AK, Fukumura D, Kim HJ, Jain RK (2021) Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat Commun 12(1):2582
Ansell SM, Flinn I, Taylor MH, Sikic BI, Brody J, Nemunaitis J, Feldman A, Hawthorne TR, Rawls T, Keler T, Yellin MJ (2020) Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies. Blood Adv 4(9):1917–1926
Armitage RJ, Maliszewski CR, Alderson MR, Grabstein KH, Spriggs MK, Fanslow WC (1993) CD40L: a multi-functional ligand. Semin Immunol 5(6):401–412
Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle A (2016) Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer 52:50–66
Bai L, Peng H, Hao X, Tang L, Sun C, Zheng M, Liu F, Lian Z, Bai L, Wei H, Sun R, Tian Z (2019) CD8(+) T cells promote maturation of liver-resident NK cells through the CD70-CD27 axis. Hepatology 70(5):1804–1815
Balmanoukian AS, Infante JR, Aljumaily R, Naing A, Chintakuntlawar AV, Rizvi NA, Ross HJ, Gordon M, Mallinder PR, Elgeioushi N, Gonzalez-Garcia I, Standifer N, Cann J, Durham N, Rahimian S, Kumar R, Denlinger CS (2020) Safety and clinical activity of MEDI1873, a novel GITR agonist, in advanced solid tumors. Clin Cancer Res 26(23):6196–6203
Barsoumian HB, Yolcu ES, Shirwan H (2016) 4-1BB signaling in conventional T cells drives IL-2 production that overcomes CD4+CD25+FoxP3+ T regulatory cell suppression. PLoS One 11(4):e0153088
Barsoumian HB, Batra L, Shrestha P, Bowen WS, Zhao H, Egilmez NK, Gomez-Gutierrez JG, Yolcu ES, Shirwan H (2019) A novel form of 4-1BBL prevents cancer development via nonspecific activation of CD4(+) T and natural killer cells. Cancer Res 79(4):783–794
Bartkowiak T, Curran MA (2015) 4-1BB agonists: multi-potent potentiators of tumor immunity. Front Oncol 5:117
Bauer TM, Chae YK, Patel S, D’Angelo SP, Blumenschein GR, Norton J, Pound C, Lanasa MC, Curti BD (2015) A phase I study of MEDI6383, an OX40 agonist, in adult patients with select advanced solid tumors. J Clin Oncol 33(15_suppl):TPS3093-TPS3093
Baumann R, Yousefi S, Simon D, Russmann S, Mueller C, Simon HU (2004) Functional expression of CD134 by neutrophils. Eur J Immunol 34(8):2268–2275
Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, Teitelbaum UR, Vonderheide RH, O’Dwyer PJ (2013) A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 19(22):6286–6295
Beck AH, Espinosa I, Edris B, Li R, Montgomery K, Zhu S, Varma S, Marinelli RJ, van de Rijn M, West RB (2009) The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res 15(3):778–787
Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393(6684):478–480
Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T (2015) Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 13:211
Bhattacharya P, Gopisetty A, Ganesh BB, Sheng JR, Prabhakar BS (2011) GM-CSF-induced, bone-marrow-derived dendritic cells can expand natural Tregs and induce adaptive Tregs by different mechanisms. J Leukoc Biol 89(2):235–249
Bjorck P, Braesch-Andersen S, Paulie S (1994) Antibodies to distinct epitopes on the CD40 molecule co-operate in stimulation and can be used for the detection of soluble CD40. Immunology 83(3):430–437
Blackstein M, Vogel CL, Ambinder R, Cowan J, Iglesias J, Melemed A (2002) Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial. Oncology 62(1):2–8
Bodmer JL, Schneider P, Tschopp J (2002) The molecular architecture of the TNF superfamily. Trends Biochem Sci 27(1):19–26
Bonnans C, Thomas G, He W, Jung B, Chen W, Liao M, Heyen J, Buetow B, Pillai S, Matsumoto D, Chaparro-Riggers J, Salek-Ardakani S, Qu Y (2020) CD40 agonist-induced IL-12p40 potentiates hepatotoxicity. J Immunother Cancer 8(1)
Borst J, Hendriks J, Xiao Y (2005) CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol 17(3):275–281
Broll K, Richter G, Pauly S, Hofstaedter F, Schwarz H (2001) CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am J Clin Pathol 115(4):543–549
Brunekreeft KL, Strohm C, Gooden MJ, Rybczynska AA, Nijman HW, Grigoleit GU, Helfrich W, Bremer E, Siegmund D, Wajant H, de Bruyn M (2014) Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death. Mol Cancer 13:85
Buchan SL, Dou L, Remer M, Booth SG, Dunn SN, Lai C, Semmrich M, Teige I, Martensson L, Penfold CA, Chan HTC, Willoughby JE, Mockridge CI, Dahal LN, Cleary KLS, James S, Rogel A, Kannisto P, Jernetz M, Williams EL, Healy E, Verbeek JS, Johnson PWM, Frendeus B, Cragg MS, Glennie MJ, Gray JC, Al-Shamkhani A, Beers SA (2018a) Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function. Immunity 49(5):958–970 e957
Buchan SL, Fallatah M, Thirdborough SM, Taraban VY, Rogel A, Thomas LJ, Penfold CA, He LZ, Curran MA, Keler T, Al-Shamkhani A (2018b) PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8(+) T-cell-driven antitumor immunity. Clin Cancer Res 24(10):2383–2394
Buechele C, Baessler T, Wirths S, Schmohl JU, Schmiedel BJ, Salih HR (2012) Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL). Leukemia 26(5):991–1000
Bullock T, McClintic H, Jeong S, Smith K, Olson W, Ramakrishna V, Vitale L, Green J, Yellin M, Davis TJJFIOC (2014) Immune correlates of varlilumab treated cancer patients are consistent with CD27 costimulatory activity. J ImmunoTher Cancer 2(S3):P100
Burocchi A, Pittoni P, Gorzanelli A, Colombo MP, Piconese S (2011) Intratumor OX40 stimulation inhibits IRF1 expression and IL-10 production by Treg cells while enhancing CD40L expression by effector memory T cells. Eur J Immunol 41(12):3615–3626
Buzzatti G, Dellepiane C, Del Mastro L (2020) New emerging targets in cancer immunotherapy: the role of GITR. ESMO Open 4(Suppl 3)
Byrne AM, Goleva E, Leung DY (2009) Identification of glucocorticoid-induced TNF receptor-related protein ligand on keratinocytes: ligation by GITR induces keratinocyte chemokine production and augments T-cell proliferation. J Invest Dermatol 129(12):2784–2794
Byrne KT, Betts CB, Mick R, Sivagnanam S, Bajor DL, Laheru DA, Chiorean EG, O’Hara MH, Liudahl SM, Newcomb C, Alanio C, Ferreira AP, Park BS, Ohtani T, Huffman AP, Vayrynen SA, Dias Costa A, Kaiser JC, Lacroix AM, Redlinger C, Stern M, Nowak JA, Wherry EJ, Cheever MA, Wolpin BM, Furth EE, Jaffee EM, Coussens LM, Vonderheide RH (2021) Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. Clin Cancer Res 27(16):4574–4586
Cai H, Wang W, Lin Z, Zhang Y, Wu B, Wan Y, Li R (2020) Recombinant costimulatory fusion proteins as functional immunomodulators enhance antitumor activity in murine B16F10 melanoma. Vaccines (Basel) 8(2)
Calvo E, Moreno V, Perets R, Yablonski-Peretz T, Fourneau N, Girgis S, Guo Y, Hellemans P, Hokey D, Pendas Franco N (2019) A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors. American Society of Clinical Oncology
Capalbo C, Scafetta G, Filetti M, Marchetti P, Bartolazzi A (2019) Predictive biomarkers for checkpoint inhibitor-based immunotherapy: the galectin-3 signature in NSCLCs. Int J Mol Sci 20(7)
Carbone E, Ruggiero G, Terrazzano G, Palomba C, Manzo C, Fontana S, Spits H, Kärre K, Zappacosta S (1997) A new mechanism of NK cell cytotoxicity activation: the CD40-CD40 ligand interaction. J Exp Med 185(12):2053–2060
Carr JM, Carrasco MJ, Thaventhiran JE, Bambrough PJ, Kraman M, Edwards AD, Al-Shamkhani A, Fearon DT (2006) CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector differentiation. Proc Natl Acad Sci U S A 103(51):19454–19459
Carrier Y, Whitters MJ, Miyashiro JS, LaBranche TP, Ramon HE, Benoit SE, Ryan MS, Keegan SP, Guay H, Douhan J, Collins M, Dunussi-Joannopoulos K, Medley QG (2012) Enhanced GITR/GITRL interactions augment IL-27 expression and induce IL-10-producing Tr-1 like cells. Eur J Immunol 42(6):1393–1404
Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72(9):3666–3670
Ceglia V, Zurawski S, Montes M, Bouteau A, Wang Z, Ellis J, Igyarto BZ, Levy Y, Zurawski G (2021) Anti-CD40 antibodies fused to CD40 ligand have superagonist properties. J Immunol 207(8):2060–2076
Cendrowicz E, Jacob L, Greenwald S, Tamir A, Gozlan Y, Huls G, Foley-Comer A, Pereg Y, Chajut A, Peled A, Bremer E (2020) DSP107, a novel bi-functional fusion protein that combines inhibition of CD47 with targeted activation of 4-1BB to trigger innate and adaptive anticancer immune responses. Blood 136(Supplement 1):19–20
Chan M, Wu L, Yun Z, McKee TD, Cabanero M, Zhao Y, Kohno M, Murakami J, de Perrot M (2021) Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma. Commun Biol 4(1):914
Chattopadhyay S, Chakraborty NG (2009) GITR expression on T-cell receptor-stimulated human CD8 T cell in a JNK-dependent pathway. Indian J Hum Genet 15(3):121–124
Chattopadhyay K, Ramagopal UA, Brenowitz M, Nathenson SG, Almo SC (2008) Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily. Proc Natl Acad Sci U S A 105(2):635–640
Chen S, Lee LF, Fisher TS, Jessen B, Elliott M, Evering W, Logronio K, Tu GH, Tsaparikos K, Li X, Wang H, Ying C, Xiong M, VanArsdale T, Lin JC (2015) Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol Res 3(2):149–160
Chen S, Fang L, Guo W, Zhou Y, Yu G, Li W, Dong K, Liu J, Luo Y, Wang B, Li Z, Zhao C, Sun Z, Shen Y, Leng Q, Zhou D, Han Z, Huang H, Ren H, Xu G, Feng X (2018) Control of Treg cell homeostasis and immune equilibrium by Lkb1 in dendritic cells. Nat Commun 9(1):5298
Chester C, Ambulkar S, Kohrt HE (2016) 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 65(10):1243–1248
Chin SM, Kimberlin CR, Roe-Zurz Z, Zhang P, Xu A, Liao-Chan S, Sen D, Nager AR, Oakdale NS, Brown C, Wang F, Yang Y, Lindquist K, Yeung YA, Salek-Ardakani S, Chaparro-Riggers J (2018) Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Nat Commun 9(1):4679
Choi BK, Kim YH, Kim CH, Kim MS, Kim KH, Oh HS, Lee MJ, Lee DK, Vinay DS, Kwon BS (2010) Peripheral 4-1BB signaling negatively regulates NK cell development through IFN-gamma. J Immunol 185(3):1404–1411
Choudhury BA, Liang JC, Thomas EK, Flores-Romo L, Xie QS, Agusala K, Sutaria S, Sinha I, Champlin RE, Claxton DF (1999) Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Blood 93(3):780–786
Claus C, Riether C, Schurch C, Matter MS, Hilmenyuk T, Ochsenbein AF (2012) CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res 72(14):3664–3676
Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, Albrecht R, Herter S, Schlenker R, Hüsser T, Diggelmann S, Challier J, Mössner E, Hosse RJ, Hofer T, Brünker P, Joseph C, Benz J, Ringler P, Stahlberg H, Lauer M, Perro M, Chen S, Küttel C, Bhavani Mohan PL, Nicolini V, Birk MC, Ongaro A, Prince C, Gianotti R, Dugan G, Whitlow CT, Solingapuram Sai KK, Caudell DL, Burgos-Rodriguez AG, Cline JM, Hettich M, Ceppi M, Giusti AM, Crameri F, Driessen W, Morcos PN, Freimoser-Grundschober A, Levitsky V, Amann M, Grau-Richards S, von Hirschheydt T, Tournaviti S, Mølhøj M, Fauti T, Heinzelmann-Schwarz V, Teichgräber V, Colombetti S, Bacac M, Zippelius A, Klein C, Umaña P (2019) Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med 11(496):eaav5989
Coe D, Begom S, Addey C, White M, Dyson J, Chai JG (2010) Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol Immunother 59(9):1367–1377
Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA, Merghoub T, Houghton AN, Wolchok JD (2010) Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One 5(5):e10436
Compte M, Harwood SL, Muñoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N (2018) A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity. Nat Commun 9(1):4809
Conrad C, Gregorio J, Wang YH, Ito T, Meller S, Hanabuchi S, Anderson S, Atkinson N, Ramirez PT, Liu YJ, Freedman R, Gilliet M (2012) Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells. Cancer Res 72(20):5240–5249
Coquet JM, Ribot JC, Babala N, Middendorp S, van der Horst G, Xiao Y, Neves JF, Fonseca-Pereira D, Jacobs H, Pennington DJ, Silva-Santos B, Borst J (2013) Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J Exp Med 210(4):715–728
Cortesi F, Delfanti G, Grilli A, Calcinotto A, Gorini F, Pucci F, Lucianò R, Grioni M, Recchia A, Benigni F, Briganti A, Salonia A, De Palma M, Bicciato S, Doglioni C, Bellone M, Casorati G, Dellabona P (2018) Bimodal CD40/Fas-dependent crosstalk between iNKT cells and tumor-associated macrophages impairs prostate cancer progression. Cell Rep 22(11):3006–3020
Croft M (2003) Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 3(8):609–620
Croft M (2010) Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol 28:57–78
Croft M (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26(3):183–190
Croft M, So T, Duan W, Soroosh P (2009) The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 229(1):173–191
Crouch E, Persson A, Chang D, Heuser J (1994) Molecular structure of pulmonary surfactant protein D (SP-D). J Biol Chem 269(25):17311–17319
Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP (2011) Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One 6(4):e19499
Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, Walker J, Gonzalez I, Meeuwsen T, Fox BA, Moudgil T, Miller W, Haley D, Coffey T, Fisher B, Delanty-Miller L, Rymarchyk N, Kelly T, Crocenzi T, Bernstein E, Sanborn R, Urba WJ, Weinberg AD (2013) OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 73(24):7189–7198
Davies AM, Chansky K, Lara PN Jr, Gumerlock PH, Crowley J, Albain KS, Vogel SJ, Gandara DR, Southwest Oncology G (2009) Bortezomib plus gemcitabine/carboplatin as first-line treatment of advanced non-small cell lung cancer: a phase II Southwest Oncology Group Study (S0339). J Thorac Oncol 4(1):87–92
Deng J, Zhao S, Zhang X, Jia K, Wang H, Zhou C, He Y (2019) OX40 (CD134) and OX40 ligand, important immune checkpoints in cancer. Onco Targets Ther 12:7347–7353
Denlinger C, Infante J, Aljumaily R, Naing A, Chintakuntlawar A, Rizvi N, Ross H, Gordon M, Kumar R, Ma M (2018) A phase I study of MEDI1873, a novel GITR agonist, in advanced solid tumors. Ann Oncol 29: viii411
Dilloo D, Brown M, Roskrow M, Zhong W, Holladay M, Holden W, Brenner M (1997) CD40 ligand induces an antileukemia immune response in vivo. Blood 90(5):1927–1933
Dong H, Buckner A, Prince J, Bullock T (2019) Frontline science: late CD27 stimulation promotes IL-7Ralpha transcriptional re-expression and memory T cell qualities in effector CD8(+) T cells. J Leukoc Biol 106(5):1007–1019
Dovedi SJ, Seaman J, Osma-Garcia I, Deschler K, Poon E, Herbst R, Wilkinson R (2018) Abstract 3820: novel PD-1/GITRL bispecific fusion protein delivering concurrent T cell co-stimulation and checkpoint pathway inhibition. Cancer Res 78(13 Supplement):3820
Drenkard D, Becke FM, Langstein J, Spruss T, Kunz-Schughart LA, Tan TE, Lim YC, Schwarz H (2007) CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity. FASEB J 21(2):456–463
Duggleby RC, Shaw TN, Jarvis LB, Kaur G, Gaston JS (2007) CD27 expression discriminates between regulatory and non-regulatory cells after expansion of human peripheral blood CD4+ CD25+ cells. Immunology 121(1):129–139
Durham NM, Holoweckyj N, MacGill RS, McGlinchey K, Leow CC, Robbins SH (2017) GITR ligand fusion protein agonist enhances the tumor antigen-specific CD8 T-cell response and leads to long-lasting memory. J Immunother Cancer 5:47
Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229(1):152–172
Ellmark P, Fritzell S, Furebring CJIPW (2018) Alligator Bioscience AB. Sweden. Bispecific polypeptides to GITR and CTLA-4. 24
El-Mesery M, Trebing J, Schäfer V, Weisenberger D, Siegmund D, Wajant H (2013) CD40-directed scFv-TRAIL fusion proteins induce CD40-restricted tumor cell death and activate dendritic cells. Cell Death Dis 4(11):e916
Elpek KG, Yolcu ES, Franke DD, Lacelle C, Schabowsky RH, Shirwan H (2007) Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling. J Immunol 179(11):7295–7304
Eskiocak U, Guzman W, Wolf B, Cummings C, Milling L, Wu HJ, Ophir M, Lambden C, Bakhru P, Gilmore DC, Ottinger S, Liu L, McConaughy WK, He SQ, Wang C, Leung CL, Lajoie J, Carson WFT, Zizlsperger N, Schmidt MM, Anderson AC, Bobrowicz P, Schuetz TJ, Tighe R (2020) Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight 5(5)
Esparza EM, Arch RH (2005) Glucocorticoid-induced TNF receptor functions as a costimulatory receptor that promotes survival in early phases of T cell activation. J Immunol 174(12):7869–7874
Esparza EM, Lindsten T, Stockhausen JM, Arch RH (2006) Tumor necrosis factor receptor (TNFR)-associated factor 5 is a critical intermediate of costimulatory signaling pathways triggered by glucocorticoid-induced TNFR in T cells. J Biol Chem 281(13):8559–8564
Faassen AE, Dalke DP, Berton MT, Warren WD, Pierce SK (1995) CD40-CD40 ligand interactions stimulate B cell antigen processing. Eur J Immunol 25(12):3249–3255
Fallarino F, Grohmann U, Vacca C, Bianchi R, Fioretti MC, Puccetti P (2002) CD40 ligand and CTLA-4 are reciprocally regulated in the Th1 cell proliferative response sustained by CD8(+) dendritic cells. J Immunol 169(3):1182–1188
Farhad M, Rolig AS, Redmond WL (2018) The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. Onco Targets Ther 7(6):e1434467
Feau S, Garcia Z, Arens R, Yagita H, Borst J, Schoenberger SP (2012) The CD4(+) T-cell help signal is transmitted from APC to CD8(+) T-cells via CD27-CD70 interactions. Nat Commun 3:948
Fehniger TA (2017) CD70 turns on NK cells to attack lymphoma. Blood 130(3):238–239
Fellermeier-Kopf S, Gieseke F, Sahin U, Muller D, Pfizenmaier K, Kontermann RE (2018) Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans. Onco Targets Ther 7(9):e1471442
Fisher TS, Kamperschroer C, Oliphant T, Love VA, Lira PD, Doyonnas R, Bergqvist S, Baxi SM, Rohner A, Shen AC, Huang C, Sokolowski SA, Sharp LL (2012) Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother 61(10):1721–1733
Fotin-Mleczek M, Henkler F, Hausser A, Glauner H, Samel D, Graness A, Scheurich P, Mauri D, Wajant H (2004) Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-kappaB activation. J Biol Chem 279(1):677–685
French RR, Taraban VY, Crowther GR, Rowley TF, Gray JC, Johnson PW, Tutt AL, Al-Shamkhani A, Glennie MJ (2007) Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood 109(11):4810–4815
Fritzell S, Levin M, Åberg I, Johansson M, Winnerstam M, Smith KE, Ellmark P, Furebring C, Norlén P, Kvarnhammar A (2019) Abstract 4077: ATOR-1144 is a tumor-directed CTLA-4 x GITR bispecific antibody that acts by depleting Tregs and activating effector T cells and NK cells. Cancer Res 79(13 Supplement):4077–4077
Fromm G, de Silva S, Johannes K, Patel A, Hornblower JC, Schreiber TH (2018) Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy. J ImmunoTher Cancer 6(1):149
Fu Z, Wang S, Li J, Zhang Y, Li H, Li G, Wan X, Zhang Y (2020) Biological role of GITR/GITRL in attributes and immune responses of macrophage. J Leukoc Biol 107(2):309–321
Fu N, Xie F, Sun Z, Wang Q (2021) The OX40/OX40L Axis regulates T follicular helper cell differentiation: implications for autoimmune diseases. Front Immunol 12:670637
Futagawa T, Akiba H, Kodama T, Takeda K, Hosoda Y, Yagita H, Okumura K (2002) Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int Immunol 14(3):275–286
Gajdasik DW, Gaspal F, Halford EE, Fiancette R, Dutton EE, Willis C, Ruckert T, Romagnani C, Gerard A, Bevington SL, MacDonald AS, Botto M, Vyse T, Withers DR (2020) Th1 responses in vivo require cell-specific provision of OX40L dictated by environmental cues. Nat Commun 11(1):3421
Garris CS, Wong JL, Ravetch JV, Knorr DA (2021) Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer. Sci Transl Med 13(594)
Garza-Morales R, Perez-Trujillo JJ, Martinez-Jaramillo E, Saucedo-Cardenas O, Loera-Arias MJ, Garcia-Garcia A, Rodriguez-Rocha H, Yolcu E, Shirwan H, Gomez-Gutierrez JG, Montes-de-Oca-Luna R (2019) A DNA vaccine encoding SA-4-1BBL fused to HPV-16 E7 antigen has prophylactic and therapeutic efficacy in a cervical cancer mouse model. Cancers 11(1):96
Gaspar M, Pravin J, Rodrigues L, Uhlenbroich S, Everett KL, Wollerton F, Morrow M, Tuna M, Brewis N (2020) A CD137/OX40 bispecific antibody induces potent antitumor activity that is dependent on target co-engagement. Cancer Immunol Res
Ge H, Mu L, Jin L, Yang C, Chang YE, Long Y, DeLeon G, Deleyrolle L, Mitchell DA, Kubilis PS, Lu D, Qi J, Gu Y, Lin Z, Huang J (2017) Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM. Int J Cancer 141(7):1434–1444
Geva R, Voskoboynik M, Dobrenkov K, Mayawala K, Gwo J, Wnek R, Chartash E, Long GV (2020) First-in-human phase 1 study of MK-1248, an anti–glucocorticoid-induced tumor necrosis factor receptor agonist monoclonal antibody, as monotherapy or with pembrolizumab in patients with advanced solid tumors. Cancer 126:4926–4935
Gieffers C, Sykora J, Merz C, Müller MR, Richards DM, Sefrin J, Billian-Frey K, Heinonen K, Marschall V, Schröder M, Fricke H, Thiemann M, Oliver H (2019) Abstract 5015: HERA-CD40L a hexavalent CD40 agonist induces T cell mediated anti-tumor immune response and shows superior activity in direct comparison to benchmark agonistic antibodies. Cancer Res 79(13 Supplement):5015
Girard M, Watts TH (2018) Fc-engineered anti-4-1BB antibodies pack a one-two punch. Immunity 49(5):791–793
Gladue RP, Paradis T, Cole SH, Donovan C, Nelson R, Alpert R, Gardner J, Natoli E, Elliott E, Shepard R, Bedian V (2011) The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice. Cancer Immunol Immunother 60(7):1009–1017
Gonzalez AM, Breous E, Manrique ML, Savitsky D, Waight J, Gombos R, Liu Y, Lin S, Leger O, Seibert V, Tsuji T, Merghoub T, Budha S, Zappasodi R, Ritter G, Wolchok J, Scherle P, Hollis G, Huber R, Van Dijk M, Stein R, Wilson N (2016a) Abstract 3220: a novel agonist antibody (INCAGN01876) that targets the costimulatory receptor GITR. Cancer Res 76(14 Supplement):3220–3220
Gonzalez AM, Manrique ML, Breous E, Savitsky D, Waight J, Gombos R, Liu Y, Lin S, Merghoub T, Hirschhorn-Cymerman D, Ritter G, Wolchok J, Scherle P, Hollis G, Huber R, Van Dijk M, Stein R, Wilson NS (2016b) Abstract 3204: INCAGN01949: an anti-OX40 agonist antibody with the potential to enhance tumor-specific T-cell responsiveness, while selectively depleting intratumoral regulatory T cells. Cancer Res 76(14 Supplement):3204–3204
Gonzalez AM, Manrique ML, Swiech L, Horn T, Breous E, Waight J, Savitsky D, Liu Y, Lin S, Clarke C (2017) INCAGN1949, an anti-OX40 antibody with an optimal agonistic profile and the ability to selectively deplete intratumoral regulatory T cells. AACR
Goodwin RG, Din WS, Davis-Smith T, Anderson DM, Gimpel SD, Sato TA, Maliszewski CR, Brannan CI, Copeland NG, Jenkins NA et al (1993) Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur J Immunol 23(10):2631–2641
Gopal AK, Levy R, Houot R, Patel SP, Popplewell L, Jacobson C, Mu XJ, Deng S, Ching KA, Chen Y, Davis CB, Huang B, Fly KD, Thall A, Woolfson A, Bartlett NL (2020) First-in-human study of utomilumab, a 4-1BB/CD137 agonist, in combination with rituximab in patients with follicular and other CD20(+) non-Hodgkin lymphomas. Clin Cancer Res 26(11):2524–2534
Gozlan YM, Hilgendorf S, Aronin A, Sagiv Y, Ben-gigi-Tamir L, Amsili S, Tamir A, Pecker I, Greenwald S, Chajut A, Foley-Comer A, Pereg Y, Peled A, Dranitzki-Elhalel M, Bremer E (2019) Abstract A076: DSP107 – a novel SIRPα-4-1BBL dual signaling protein (DSP) for cancer immunotherapy. Cancer Immunol Res 7(2 Supplement):A076
Graf D, Muller S, Korthauer U, van Kooten C, Weise C, Kroczek RA (1995) A soluble form of TRAP (CD40 ligand) is rapidly released after T cell activation. Eur J Immunol 25(6):1749–1754
Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M (2000) The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol 165(6):3043–3050
Grammer AC, Bergman MC, Miura Y, Fujita K, Davis LS, Lipsky PE (1995) The CD40 ligand expressed by human B cells costimulates B cell responses. J Immunol 154(10):4996–5010
Gruss HJ, Ulrich D, Braddy S, Armitage RJ, Dower SK (1995) Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed-Sternberg cells. Eur J Immunol 25(7):2083–2089
Gunde T, Brock M, Warmuth S, Simonin A, Hess C, Oswald E, Tietz J, Zeberer J, Mahler D, Muntwiler S (2019) A novel, monovalent tri-specific antibody-based molecule that simultaneously modulates PD-L1 and 4-1BB exhibits potent anti-tumoral activity in vivo. SEA 2(109):40000
Guo Y, Yang L, Lei S, Tan W, Long J (2019) NEDD4 negatively regulates GITR via ubiquitination in immune microenvironment of melanoma. Onco Targets Ther 12:10629–10637
Hamano R, Huang J, Yoshimura T, Oppenheim JJ, Chen X (2011) TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. Eur J Immunol 41(7):2010–2020
Hamid O, Thompson JA, Diab A, Ros W, Eskens F, Bermingham C, Konto C, Long H, Liao K, Ganguly BJ (2016) First in human (FIH) study of an OX40 agonist monoclonal antibody (mAb) PF-04518600 (PF-8600) in adult patients (pts) with select advanced solid tumors: preliminary safety and pharmacokinetic (PK)/pharmacodynamic results. American Society of Clinical Oncology
Hammer B, Bawadekar M, Bissen M, Painter J, Lehmann L, Li FQ, Bailey L, Glaser B, Green R (2019) Abstract 563: a biparatopic agonist antibody for OX40 that exhibits superior activity without secondary crosslinking. Cancer Res 79(13 Supplement):563–563
Hanabuchi S, Watanabe N, Wang YH, Wang YH, Ito T, Shaw J, Cao W, Qin FX, Liu YJ (2006) Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL). Blood 107(9):3617–3623
Hansen AR, Infante JR, McArthur G, Gordon MS, Lesokhin AM, Stayner A-L, Bauer TM, Sandhu S, Tsai F, Snyder A, Subramaniam DS, Kim J, Stefanich E, Li C-C, Ruppel J, Anderson M, Gilbert H, McCall B, Huseni MA, Rhee I, Pishvaian M (2016) Abstract CT097: A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumors. Cancer Res 76(14 Supplement):CT097–CT097
Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B, Giese T, Gires O, Endres S, Hartmann G (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 63(19):6478–6487
Hashimoto K (2021) CD137 as an attractive T cell co-stimulatory target in the TNFRSF for immuno-oncology drug development. Cancers (Basel) 13(10)
Haswell LE, Glennie MJ, Al-Shamkhani A (2001) Analysis of the oligomeric requirement for signaling by CD40 using soluble multimeric forms of its ligand, CD154. Eur J Immunol 31(10):3094–3100
He L-Z, Prostak N, Thomas LJ, Vitale L, Weidlick J, Crocker A, Pilsmaker CD, Round SM, Tutt A, Glennie MJ, Marsh H, Keler T (2013) Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27–transgenic mice. J Immunol 191(8):4174–4183
He Y, van Bommel PE, Samplonius DF, Bremer E, Helfrich W (2017) A versatile pretargeting approach for tumour-selective delivery and activation of TNF superfamily members. Sci Rep 7(1):13301
He Y, Vlaming M, van Meerten T, Bremer EJC (2022) The implementation of TNFRSF co-stimulatory domains in CAR-T cells for optimal functional activity. Cancers 14(2):299
Hendriks J, Gravestein LA, Tesselaar K, van Lier RA, Schumacher TN, Borst J (2000) CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol 1(5):433–440
Hewitt SL, Bai A, Bailey D, Ichikawa K, Zielinski J, Karp R, Apte A, Arnold K, Zacharek SJ, Iliou MS, Bhatt K (2019) Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. Sci Transl Med 11(477):eaat9143
Hinner MJ, Aiba RSB, Jaquin TJ, Berger S, Dürr MC, Schlosser C, Allersdorfer A, Wiedenmann A, Matschiner G, Schüler J, Moebius U, Rothe C, Matis L, Olwill SA (2019) Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-anticalin fusion PRS-343. Clin Cancer Res 25(19):5878–5889
Hoffmann A, Baltimore D (2006) Circuitry of nuclear factor kappaB signaling. Immunol Rev 210:171–186
Hornero RA, Georgiadis C, Hua P, Trzupek D, He L-Z, Qasim W, Todd JA, Ferreira RC, Wood KJ, Issa F (2020) CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells. Commun Biol 3(1):1–17
Hoshino A, Tanaka Y, Akiba H, Asakura Y, Mita Y, Sakurai T, Takaoka A, Nakaike S, Ishii N, Sugamura K, Yagita H, Okumura K (2003) Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma. Eur J Immunol 33(4):861–869
Houot R, Goldstein MJ, Kohrt HE, Myklebust JH, Alizadeh AA, Lin JT, Irish JM, Torchia JA, Kolstad A, Chen L, Levy R (2009) Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion. Blood 114(16):3431–3438
Houtenbos I, Santegoets S, Westers TM, Waisfisz Q, Kipriyanov S, Denkers F, Scheper RJ, de Gruijl TD, Ossenkoppele GJ, van de Loosdrecht AA (2008) The novel bispecific diabody alphaCD40/alphaCD28 strengthens leukaemic dendritic cell-induced T-cell reactivity. Br J Haematol 142(2):273–283
Hutchings M (2020) Phase 1 study of CD19 targeted 4-1BBL costimulatory agonist to enhance T cell (glofitamab combination) or NK cell effector function (obinutuzumab combination) in relapsed/refractory B cell lymphoma
Imura A, Hori T, Imada K, Ishikawa T, Tanaka Y, Maeda M, Imamura S, Uchiyama T (1996) The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J Exp Med 183(5):2185–2195
Infante JR, Hansen AR, Pishvaian MJ, Chow LQM, McArthur GA, Bauer TM, Liu SV, Sandhu SK, Tsai FY-C, Kim J, Stefanich E, Li C-C, Gilbert H, Mccall B, Anderson MS, Huseni M, Rhee IP, Siu LL, Gordon MS (2016) A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol 34(15_suppl):101–101
Inhibrx Reports Fourth Quarter and Fiscal Year 2020 Financial results and announces phase 1 single agent dose escalation results for INBRX-105, a novel targeted 4-1BB agonist
Irenaeus SMM, Nielsen D, Ellmark P, Yachnin J, Deronic A, Nilsson A, Norlen P, Veitonmaki N, Wennersten CS, Ullenhag GJ (2019) First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies. Int J Cancer 145(5):1189–1199
Ishikawa K, Miyamoto M, Yoshioka T, Kato T, Kaji M, Ohbuchi T, Hirano S, Itoh T, Dosaka-Akita H, Kondo S (2008) Up-regulation of CD40 with juxtacrine activity in human nonsmall lung cancer cells correlates with poor prognosis. Cancer 113(3):530–541
Ito D, Ogasawara K, Iwabuchi K, Inuyama Y, Onoé K (2000) Induction of CTL responses by simultaneous administration of liposomal peptide vaccine with anti-CD40 and anti-CTLA-4 mAb. J Immunol 164(3):1230–1235
Ito T, Wang YH, Duramad O, Hanabuchi S, Perng OA, Gilliet M, Qin FX, Liu YJ (2006) OX40 ligand shuts down IL-10-producing regulatory T cells. Proc Natl Acad Sci U S A 103(35):13138–13143
Jak M, Mous R, Remmerswaal EB, Spijker R, Jaspers A, Yague A, Eldering E, Van Lier RA, Van Oers MH (2009) Enhanced formation and survival of CD4+ CD25hi Foxp3+ T-cells in chronic lymphocytic leukemia. Leuk Lymphoma 50(5):788–801
Jeong S, Park E, Kim HD, Sung E, Kim H, Jeon J, Kim Y, Jung UJ, Son YG, Hong Y, Lee H, Lee S, Lim Y, Won J, Jeon M, Hwang S, Fang L, Jiang W, Wang Z, Shin EC, Park SH, Jung J (2021) Novel anti-4-1BBxPD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade. J Immunother Cancer 9(7)
Jilaveanu LB, Sznol J, Aziz SA, Duchen D, Kluger HM, Camp RL (2012) CD70 expression patterns in renal cell carcinoma. Hum Pathol 43(9):1394–1399
Kamat AM, Colombel M, Sundi D, Lamm D, Boehle A, Brausi M, Buckley R, Persad R, Palou J, Soloway M, Witjes JA (2017) BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nat Rev Urol 14(4):244–255
Kanamaru F, Youngnak P, Hashiguchi M, Nishioka T, Takahashi T, Sakaguchi S, Ishikawa I, Azuma M (2004) Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol 172(12):7306–7314
Katakam AK, Brightbill H, Franci C, Kung C, Nunez V, Jones C 3rd, Peng I, Jeet S, Wu LC, Mellman I, Delamarre L, Austin CD (2015) Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells. Proc Natl Acad Sci U S A 112(47):14664–14669
Katakura Y, Zhuang G, Nakatani T, Furuta T, Omasa T, Kishimoto M, Suga K-I, Shioya SJJOMCBE (2004) A practical kinetic model for efficient isolation of useful antibodies from phage display libraries. J Mol Catal B 28(4–6):191–200
Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T (1998) Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation. J Biol Chem 273(10):5808–5814
Kedl RM, Jordan M, Potter T, Kappler J, Marrack P, Dow S (2001) CD40 stimulation accelerates deletion of tumor-specific CD8(+) T cells in the absence of tumor-antigen vaccination. Proc Natl Acad Sci U S A 98(19):10811–10816
Kelly JM, Darcy PK, Markby JL, Godfrey DI, Takeda K, Yagita H, Smyth MJ (2002) Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat Immunol 3(1):83–90
Kim DH, Chang WS, Lee YS, Lee KA, Kim YK, Kwon BS, Kang CY (2008) 4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation. J Immunol 180(4):2062–2068
Kim YH, Shin SM, Choi BK, Oh HS, Kim CH, Lee SJ, Kim KH, Lee DG, Park SH, Kwon BS (2015) Authentic GITR signaling fails to induce tumor regression unless Foxp3+ regulatory T cells are depleted. J Immunol 195(10):4721–4729
Kim HD, Park S, Jeong S, Lee YJ, Lee H, Kim CG, Kim KH, Hong SM, Lee JY, Kim S, Kim HK, Min BS, Chang JH, Ju YS, Shin EC, Song GW, Hwang S, Park SH (2020) 4-1BB delineates distinct activation status of exhausted tumor-infiltrating CD8(+) T cells in hepatocellular carcinoma. Hepatology 71(3):955–971
Knee DA, Hewes B, Brogdon JL (2016) Rationale for anti-GITR cancer immunotherapy. Eur J Cancer 67:1–10
Knorr DA, Dahan R, Ravetch JV (2018) Toxicity of an fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc Natl Acad Sci U S A 115(43):11048–11053
Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, Shimizu J, Nomura T, Chiba T, Sakaguchi S (2005) Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 202(7):885–891
Koh CH, Kim IK, Shin KS, Jeon I, Song B, Lee JM, Bae EA, Seo H, Kang TS, Kim BS, Chung Y, Kang CY (2020) GITR agonism triggers antitumor immune responses through IL21-expressing follicular helper T cells. Cancer Immunol Res 8(5):698–709
Kohrt HE, Houot R, Goldstein MJ, Weiskopf K, Alizadeh AA, Brody J, Muller A, Pachynski R, Czerwinski D, Coutre S, Chao MP, Chen L, Tedder TF, Levy R (2011) CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood 117(8):2423–2432
Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, Colevas AD, Weng WK, Clarke MF, Carlson RW, Stockdale FE, Mollick JA, Chen L, Levy R (2012) Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest 122(3):1066–1075
Kosmides AK, Sidhom JW, Fraser A, Bessell CA, Schneck JP (2017) Dual targeting nanoparticle stimulates the immune system to inhibit tumor growth. ACS Nano 11(6):5417–5429
Kotanides H, Sattler RM, Lebron MB, Carpenito C, Shen J, Li J, Surguladze D, Haidar JN, Burns C, Shen L, Inigo I, Pennello AL, Forest A, Chen X, Chin D, Sonyi A, Topper M, Boucher L, Sharma P, Zhang Y, Burtrum D, Novosiadly RD, Ludwig DL, Plowman GD, Kalos M (2020) Characterization of 7A5: a human CD137 (4-1BB) receptor binding monoclonal antibody with differential agonist properties that promotes antitumor immunity. Mol Cancer Ther 19(4):988–998
Kuang Z, Jing H, Wu Z, Wang J, Li Y, Ni H, Zhang P, Wu W, Wu M, Zhou S, Qiu X, Wu D, Prinz B, Baruah H, Chen B, Yu M, Liu J (2020a) Development and characterization of a novel anti-OX40 antibody for potent immune activation. Cancer Immunol Immunother 69(6):939–950
Kuang Z, Pu P, Wu M, Wu Z, Wang L, Li Y, Zhang S, Jing H, Wu W, Chen BJMCT (2020b) A novel bispecific antibody with PD-L1–assisted OX40 activation for cancer treatment. Mol Cancer Ther 19(12):2564–2574
Kurche JS, Haluszczak C, McWilliams JA, Sanchez PJ, Kedl RM (2012) Type I IFN-dependent T cell activation is mediated by IFN-dependent dendritic cell OX40 ligand expression and is independent of T cell IFNR expression. J Immunol 188(2):585–593
Kvarnhammar AM, Veitonmaki N, Hagerbrand K, Dahlman A, Smith KE, Fritzell S, von Schantz L, Thagesson M, Werchau D, Smedenfors K, Johansson M, Rosen A, Aberg I, Winnerstam M, Nyblom E, Barchan K, Furebring C, Norlen P, Ellmark P (2019) The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J Immunother Cancer 7(1):103
Labiano S, Roh V, Godfroid C, Hiou-Feige A, Romero J, Sum E, Rapp M, Boivin G, Wyss T, Simon C, Bourhis J, Umana P, Trumpfheller C, Tolstonog GV, Vozenin MC, Romero P (2021) CD40 agonist targeted to fibroblast activation protein alpha synergizes with radiotherapy in murine HPV-positive head and neck tumors. Clin Cancer Res 27(14):4054–4065
Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, Combes JD, Faget J, Mithieux F, Cassignol A, Tredan O, Durand I, Menetrier-Caux C, Caux C, Blay JY, Ray-Coquard I, Bendriss-Vermare N (2011) Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 71(16):5423–5434
Lathrop SK, Huddleston CA, Dullforce PA, Montfort MJ, Weinberg AD, Parker DC (2004) A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. J Immunol 172(11):6735–6743
Leblond MM, Tillé L, Nassiri S, Gilfillan CB, Imbratta C, Schmittnaegel M, Ries CH, Speiser DE, Verdeil G (2020) CD40 agonist restores the antitumor efficacy of anti-PD1 therapy in muscle-invasive bladder cancer in an IFN I/II-mediated manner. Cancer Immunol Res 8:1180–1192
Lee SW, Croft M (2009) 4-1BB as a therapeutic target for human disease. Adv Exp Med Biol 647:120–129
Lee S-H, Hahm D (2016) The effects of agonistic α-4-1BB antibody on natural killer cell function. J Immunol 196(1 Supplement):61.64-61.64
Leidner RS, Patel SP, Fury MG, Ferris RL, McDevitt JT, Lanasa MC, Glisson BS (2015) A phase I study to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of MEDI0562 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 33(15_suppl):TPS6083-TPS6083
Leyland R, Watkins A, Mulgrew KA, Holoweckyj N, Bamber L, Tigue NJ, Offer E, Andrews J, Yan L, Mullins S, Oberst MD, Coates Ulrichsen J, Leinster DA, McGlinchey K, Young L, Morrow M, Hammond SA, Mallinder P, Herath A, Leow CC, Wilkinson RW, Stewart R (2017) A novel murine GITR ligand fusion protein induces antitumor activity as a monotherapy that is further enhanced in combination with an OX40 agonist. Clin Cancer Res 23(13):3416–3427
Liu Z, Hao X (2017) Intratumoral delivery of tumor antigen-loaded DC and tumor-primed CD4(+) T cells combined with agonist α-GITR mAb promotes durable CD8(+) T-cell-dependent antitumor immunity. OncoImmunology 6(6):e1315487
Liu B, Li Z, Mahesh SP, Pantanelli S, Hwang FS, Siu WO, Nussenblatt RB (2008a) Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis. J Biol Chem 283(13):8202–8210
Liu GZ, Gomes AC, Fang LB, Gao XG, Hjelmstrom P (2008b) Decreased 4-1BB expression on CD4+CD25 high regulatory T cells in peripheral blood of patients with multiple sclerosis. Clin Exp Immunol 154(1):22–29
Liu B, Yu H, Sun G, Sun X, Jin H, Zhang C, Shi W, Tian D, Liu K, Xu H, Li X, Yin J, Hong X, Zhang D (2017) OX40 promotes obesity-induced adipose inflammation and insulin resistance. Cell Mol Life Sci 74(20):3827–3840
Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X (2014) Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J Transl Med 12:36
Lu L, Liu N, Fan K, Zhang G, Li C, Yan Y, Liu T, Fu WH (2019) A tetravalent single chain diabody (CD40/HER2) efficiently inhibits tumor proliferation through recruitment of T cells and anti-HER2 functions. Mol Immunol 109:149–156
Luke JJ, Barlesi F, Chung K, Tolcher AW, Kelly K, Hollebecque A, Le Tourneau C, Subbiah V, Tsai F, Kao S, Cassier PA, Khasraw M, Kindler HL, Fang H, Fan F, Allaire K, Patel M, Ye S, Chao DT, Henner WR, Hayflick JS, McDevitt MA, Fong L (2021) Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors. J Immunother Cancer 9(2)
Mach F, Schönbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS, Libby P (1997) Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A 94(5):1931–1936
Madireddi S, Schabowsky R-H, Srivastava AK, Sharma RK, Yolcu ES, Shirwan H (2012) SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ. PLoS One 7(8):e42459
Mahne AE, Mauze S, Joyce-Shaikh B, Xia J, Bowman EP, Beebe AM, Cua DJ, Jain R (2017) Dual roles for regulatory T-cell depletion and costimulatory signaling in agonistic GITR targeting for tumor immunotherapy. Cancer Res 77(5):1108–1118
Maier B, Leader AM, Chen ST, Tung N, Chang C, LeBerichel J, Chudnovskiy A, Maskey S, Walker L, Finnigan JP, Kirkling ME, Reizis B, Ghosh S, D’Amore NR, Bhardwaj N, Rothlin CV, Wolf A, Flores R, Marron T, Rahman AH, Kenigsberg E, Brown BD, Merad M (2020) A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580(7802):257–262
Malhotra D, Turman S, McGlinchey K, Wang Y, Wang Y (2020) Abstract 2267: MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen-presenting cells and promotes robust anti-tumor immune responses in both hot and cold murine tumor models. Cancer Res 80(16 Supplement):2267–2267
Mangsbo SM, Broos S, Fletcher E, Veitonmaki N, Furebring C, Dahlen E, Norlen P, Lindstedt M, Totterman TH, Ellmark P (2015) The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin Cancer Res 21(5):1115–1126
Marigo I, Zilio S, Desantis G, Mlecnik B, Agnellini AHR, Ugel S, Sasso MS, Qualls JE, Kratochvill F, Zanovello P, Molon B, Ries CH, Runza V, Hoves S, Bilocq AM, Bindea G, Mazza EMC, Bicciato S, Galon J, Murray PJ, Bronte V (2016) T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30(3):377–390
Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445(7130):931–935
Massarelli E, Segal N, Ribrag V, Melero I, Gangadhar T, Urba WJJIC (2016) Clinical safety and efficacy assessment of the CD137 agonist urelumab alone and in combination with nivolumab in patients with hematologic and solid tumor malignancies. 4(Suppl 1):O7
Medler J, Wajant H (2019) Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target. Expert Opin Ther Targets 23(4):295–307
Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, Mittler RS, Chen L (1997) Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 3(6):682–685
Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L (1998) NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol 190(2):167–172
Menk AV, Scharping NE (2018) 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med 215(4):1091–1100
Merz C, Sykora J, Marschall V, Richards DM, Heinonen K, Redondo Muller M, Thiemann M, Schnyder T, Fricke H, Hill O, Gieffers C (2018) The hexavalent CD40 agonist HERA-CD40L induces T-cell-mediated antitumor immune response through activation of antigen-presenting cells. J Immunother 41(9):385–398
Mikkelsen K, Harwood SL, Compte M, Merino N, Mølgaard K, Lykkemark S, Alvarez-Mendez A, Blanco FJ, Álvarez-Vallina L (2019) Carcinoembryonic antigen (CEA)-specific 4-1BB-costimulation induced by CEA-targeted 4-1BB-agonistic trimerbodies. Front Immunol 10:1791
Millan-Perez Pena L, Martin PS, Herrera-Camacho I, Bandala C, Anaya-Ruiz M (2020) Colon carcinoma treatment using bispecific anti-GITR/CTLA-4 antibodies: a patent evaluation of WO2018091739. Expert Opin Ther Pat 30(5):307–311
Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73(3):1128–1141
Mitsui J, Nishikawa H, Muraoka D, Wang L, Noguchi T, Sato E, Kondo S, Allison JP, Sakaguchi S, Old LJ, Kato T, Shiku H (2010) Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res 16(10):2781–2791
Mo S, Gu L, Xu W, Liu J, Ding D, Wang Z, Yang J, Kong L, Zhao Y (2020) Bifunctional macromolecule activating both OX40 and interferon-alpha signaling displays potent therapeutic effects in mouse HBV and tumor models. Int Immunopharmacol 89(Pt B):107099
Montler R, Bell RB, Thalhofer C, Leidner R, Feng Z, Fox BA, Cheng AC, Bui TG, Tucker C, Hoen H, Weinberg A (2016) OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. Clin Transl Immunol 5(4):e70
Müller D, Frey K, Kontermann RE (2008) A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. J Immunother 31(8):714–722
Muller N, Wyzgol A, Munkel S, Pfizenmaier K, Wajant H (2008) Activity of soluble OX40 ligand is enhanced by oligomerization and cell surface immobilization. FEBS J 275(9):2296–2304
Nadiri A, Polyak MJ, Jundi M, Alturaihi H, Reyes-Moreno C, Hassan GS, Mourad W (2011) CD40 translocation to lipid rafts: signaling requirements and downstream biological events. Eur J Immunol 41(8):2358–2367
Naito M, Hainz U, Burkhardt UE, Fu B, Ahove D, Stevenson KE, Rajasagi M, Zhu B, Alonso A, Witten E, Matsuoka K, Neuberg D, Duke-Cohan JS, Wu CJ, Freeman GJ (2013) CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunol Immunother 62(2):347–357
Narumi K, Miyakawa R, Shibasaki C, Henmi M, Mizoguchi Y, Ueda R, Hashimoto H, Hiraoka N (2019) Local administration of GITR agonistic antibody induces a stronger antitumor immunity than systemic delivery. Sci Rep 9(1):5562
Nelke J, Medler J, Weisenberger D, Beilhack A, Wajant H (2020) CD40- and CD95-specific antibody single chain-Baff fusion proteins display BaffR-, TACI- and BCMA-restricted agonism. MAbs 12(1):1807721
Nocentini G, Riccardi C (2009) GITR: a modulator of immune response and inflammation. Adv Exp Med Biol 647:156–173
Nocentini G, Giunchi L, Ronchetti S, Krausz LT, Bartoli A, Moraca R, Migliorati G, Riccardi C (1997) A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci U S A 94(12):6216–6221
Nuebling T, Schumacher CE, Hofmann M, Hagelstein I, Schmiedel BJ, Maurer S, Federmann B, Rothfelder K, Roerden M, Dorfel D, Schneider P, Jung G, Salih HR (2018) The immune checkpoint modulator OX40 and its ligand OX40L in NK-cell immunosurveillance and acute myeloid leukemia. Cancer Immunol Res 6(2):209–221
Oberst MD, Auge C, Morris C, Kentner S, Mulgrew K, McGlinchey K, Hair J, Hanabuchi S, Du Q, Damschroder M, Feng H, Eck S, Buss N, de Haan L, Pierce AJ, Park H, Sylwester A, Axthelm MK, Picker L, Morris NP, Weinberg A, Hammond SA (2018) Potent immune modulation by MEDI6383, an engineered human OX40 ligand IgG4P Fc fusion protein. Mol Cancer Ther 17(5):1024–1038
Ochoa MC, Perez-Ruiz E, Minute L, Onate C, Perez G, Rodriguez I, Zabaleta A, Alignani D, Fernandez-Sendin M, Lopez A, Muntasell A, Sanmamed MF, Paiva B, Lopez-Botet M, Berraondo P, Melero I (2019) Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells. Onco Targets Ther 8(7):1599636
Ohshima Y, Tanaka Y, Tozawa H, Takahashi Y, Maliszewski C, Delespesse G (1997) Expression and function of OX40 ligand on human dendritic cells. J Immunol 159(8):3838–3848
Oja AE, Brasser G, Slot E, van Lier RAW, Pascutti MF, Nolte MA (2020) GITR shapes humoral immunity by controlling the balance between follicular T helper cells and regulatory T follicular cells. Immunol Lett 222:73–79
Ou W, Jiang L, Thapa RK, Soe ZC, Poudel K, Chang JH, Ku SK, Choi HG, Yong CS, Kim JO (2018) Combination of NIR therapy and regulatory T cell modulation using layer-by-layer hybrid nanoparticles for effective cancer photoimmunotherapy. Theranostics 8(17):4574
Palazon A, Teijeira A, Martinez-Forero I, Hervas-Stubbs S, Roncal C, Penuelas I, Dubrot J, Morales-Kastresana A, Perez-Gracia JL, Ochoa MC, Ochoa-Callejero L, Martinez A, Luque A, Dinchuk J, Rouzaut A, Jure-Kunkel M, Melero I (2011) Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res 71(3):801–811
Palazon A, Martinez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, Perez-Gracia JL, Penuelas I, Hervas-Stubbs S, Rouzaut A, de Landazuri MO, Jure-Kunkel M, Aragones J, Melero I (2012) The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov 2(7):608–623
Palmer DH, Hussain SA, Ganesan R, Cooke PW, Wallace DM, Young LS, James ND (2004) CD40 expression in prostate cancer: a potential diagnostic and therapeutic molecule. Oncol Rep 12(4):679–682
Pan PY, Zang Y, Weber K, Meseck ML, Chen SH (2002) OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther 6(4):528–536
Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, Divino CM, Chen SH (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70(1):99–108
Papadopoulos KP, Autio KA, Golan T, Dobrenkov K, Chartash E, Li XN, Wnek R, Long GV (2019) Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors. J Clin Oncol 37(15_suppl):9509–9509
Pedroza-Gonzalez A, Zhou G, Singh SP, Boor PP, Pan Q, Grunhagen D, de Jonge J, Tran TK, Verhoef C, Janssen IJJNH, Biermann K, Kwekkeboom J, Sprengers D (2015) GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo. Onco Targets Ther 4(12):e1051297
Peperzak V, Xiao Y, Veraar EA, Borst J (2010) CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production. J Clin Invest 120(1):168–178
Peperzak V, Veraar EA, Xiao Y, Babala N, Thiadens K, Brugmans M, Borst J (2013) CD8+ T cells produce the chemokine CXCL10 in response to CD27/CD70 costimulation to promote generation of the CD8+ effector T cell pool. J Immunol 191(6):3025–3036
Perrot I, Blanchard D, Freymond N, Isaac S, Guibert B, Pachéco Y, Lebecque S (2007) Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol 178(5):2763–2769
Pich C, Sarrabayrouse G, Teiti I, Mariame B, Rochaix P, Lamant L, Favre G, Maisongrosse V, Tilkin-Mariame AF (2016) Melanoma-expressed CD70 is involved in invasion and metastasis. Br J Cancer 114(1):63–70
Piechutta M, Berghoff AS (2019) New emerging targets in cancer immunotherapy: the role of cluster of differentiation 40 (CD40/TNFR5). ESMO Open 4(Suppl 3):e000510
Piha-Paul SA, Geva R, Tan TJ, Lim DW, Hierro C, Doi T, Rahma O, Lesokhin A, Luke JJ, Otero J, Nardi L, Singh A, Xyrafas A, Chen X, Mataraza J, Bedard PL (2021) First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas. J Immunother Cancer 9(8)
Polesso F, Sarker M, Weinberg AD, Murray SE, Moran AE (2019) OX40 agonist tumor immunotherapy does not impact regulatory T cell suppressive function. J Immunol 203(7):2011–2019
Poropatich K, Dominguez D, Chan WC, Andrade J, Zha Y, Wray B, Miska J, Qin L, Cole L, Coates S, Patel U, Samant S, Zhang B (2020) OX40+ plasmacytoid dendritic cells in the tumor microenvironment promote antitumor immunity. J Clin Invest
Postel-Vinay S, Lam VK, Ros W, Bauer TM, Hansen AR, Cho DC, Hodi FS, Schellens JH, Litton JK, Aspeslagh S (2020) Abstract CT150: a first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998)+/−pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1). AACR
Powderly JD, Tolcher A, LoRusso P, Blaney ME, Dacosta D, Henner WR, McDevitt MA, Miller KD, Golan T (2020) A phase I study of CD40 agonist ABBV-927 plus OX40 agonist ABBV-368 with or without the PD-1 inhibitor budigalimab in patients with advanced solid tumors. J Clin Oncol 38(15_suppl):TPS3147-TPS3147
Qi X, Li F, Wu Y, Cheng C, Han P, Wang J, Yang X (2019) Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcgammaR affinity. Nat Commun 10(1):2141
Qian Y, Zhao Z, Jiang Z, Li X (2002) Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells. Proc Natl Acad Sci U S A 99(14):9386–9391
Ramakrishna V, Sundarapandiyan K, Zhao B, Bylesjo M, Marsh HC, Keler T (2015) Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J Immunother Cancer 3:37
Ramakrishnan P, Wang W, Wallach D (2004) Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase. Immunity 21(4):477–489
Ramirez-Montagut T, Chow A, Hirschhorn-Cymerman D, Terwey TH, Kochman AA, Lu S, Miles RC, Sakaguchi S, Houghton AN, van den Brink MR (2006) Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity. J Immunol 176(11):6434–6442
Redmond WL, Ruby CE, Weinberg AD (2009) The role of OX40-mediated co-stimulation in T-cell activation and survival. Crit Rev Immunol 29(3):187–201
Reithofer M, Rosskopf S, Leitner J, Battin C, Bohle B, Steinberger P, Jahn-Schmid B (2021) 4-1BB costimulation promotes bystander activation of human CD8 T cells. Eur J Immunol 51(3):721–733
Reizis B (2019) Plasmacytoid dendritic cells: development, regulation, and function. Immunity 50(1):37–50
Remedios KA, Zirak B, Rosenblum MD (2017) Elucidating the role of CD27 in Treg function during Th17 responses. J Immunol 198(1 Supplement):220.220-220.220
Rentsch CA, Biot C, Gsponer JR, Bachmann A, Albert ML, Breban R (2013) BCG-mediated bladder cancer immunotherapy: identifying determinants of treatment response using a calibrated mathematical model. PLoS One 8(2):e56327
Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G, Lorigan P, Kendra KL, Maio M, Trefzer U, Smylie M, McArthur GA, Dreno B, Nathan PD, Mackiewicz J, Kirkwood JM, Gomez-Navarro J, Huang B, Pavlov D, Hauschild A (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 31(5):616–622
Richards DM, Marschall V, Billian-Frey K, Heinonen K, Merz C, Redondo Muller M, Sefrin JP, Schroder M, Sykora J, Fricke H, Hill O, Gieffers C, Thiemann M (2019) HERA-GITRL activates T cells and promotes anti-tumor efficacy independent of FcgammaR-binding functionality. J Immunother Cancer 7(1):191
Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393(6684):474–478
Riether C, Schürch CM, Flury C, Hinterbrandner M, Drück L, Huguenin AL, Baerlocher GM, Radpour R, Ochsenbein AF (2015) Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling. Sci Transl Med 7(298):298ra119
Riether C, Schurch CM, Buhrer ED, Hinterbrandner M, Huguenin AL, Hoepner S, Zlobec I, Pabst T, Radpour R, Ochsenbein AF (2017) CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med 214(2):359–380
Roberts DJ, Franklin NA, Kingeter LM, Yagita H, Tutt AL, Glennie MJ, Bullock TN (2010) Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. J Immunother 33(8):769–779
Roberts NJ, Zhou S, Diaz LA Jr, Holdhoff M (2011) Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2(10):739–751
Rogers PR, Song J, Gramaglia I, Killeen N, Croft M (2001) OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15(3):445–455
Ronchetti S, Nocentini G, Bianchini R, Krausz LT, Migliorati G, Riccardi C (2007) Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells. J Immunol 179(9):5916–5926
Ronchetti S, Ricci E, Petrillo MG, Cari L, Migliorati G, Nocentini G, Riccardi C (2015) Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells. J Immunol Res 2015:171520
Rosenzweig M, Ponte J, Apostolou I, Doty D, Guild J, Slavonic M, Ponath P, Vaickus L (2010) Development of TRX518, an aglycosyl humanized monoclonal antibody (Mab) agonist of huGITR. J Clin Oncol 28(15_suppl):e13028–e13028
Ruby CE, Yates MA, Hirschhorn-Cymerman D, Chlebeck P, Wolchok JD, Houghton AN, Offner H, Weinberg AD (2009) Cutting edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J Immunol 183(8):4853–4857
Rüter J, Antonia SJ, Burris HA, Huhn RD, Vonderheide RH (2010) Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther 10(10):983–993
Sakanishi T, Yagita H (2010) Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice. Biochem Biophys Res Commun 393(4):829–835
Sallets A, Robinson S, Kardosh A, Levy R (2018) Enhancing immunotherapy of STING agonist for lymphoma in preclinical models. Blood Adv 2(17):2230–2241
Sanborn RE, Pishvaian MJ, Callahan MK, Weise AM, Sikic BI, Rahma OE, Cho DC, Rizvi NA, Bitting RL, Starodub A (2018) Anti-CD27 agonist antibody varlilumab (varli) with nivolumab (nivo) for colorectal (CRC) and ovarian (OVA) cancer: phase (Ph) 1/2 clinical trial results. American Society of Clinical Oncology
Sato T, Ishii N, Murata K, Kikuchi K, Nakagawa S, Ndhlovu LC, Sugamura K (2002) Consequences of OX40-OX40 ligand interactions in langerhans cell function: enhanced contact hypersensitivity responses in OX40L-transgenic mice. Eur J Immunol 32(11):3326–3335
Schabowsky RH, Elpek KG, Madireddi S, Sharma RK, Yolcu ES, Bandura-Morgan L, Miller R, MacLeod KJ, Mittler RS, Shirwan H (2009) A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity. Vaccine 28(2):512–522
Schaer DA, Budhu S, Liu C, Bryson C, Malandro N, Cohen A, Zhong H, Yang X, Houghton AN, Merghoub T, Wolchok JD (2013) GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol Res 1(5):320–331
Schetters STT, Rodriguez E, Kruijssen LJW, Crommentuijn MHW, Boon L, Van den Bossche J, Den Haan JMM, Van Kooyk Y (2020) Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy. J Immunother Cancer 8(2)
Schmiedel BJ, Werner A, Steinbacher J, Nuebling T, Buechele C, Grosse-Hovest L, Salih HR (2013) Generation and preclinical characterization of a Fc-optimized GITR-Ig fusion protein for induction of NK cell reactivity against leukemia. Mol Ther 21(4):877–886
Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393(6684):480–483
Schwabe RF, Hess S, Johnson JP, Engelmann H (1997) Modulation of soluble CD40 ligand bioactivity with anti-CD40 antibodies. Hybridoma 16(3):217–226
Sefrin JP, Richards DM, Billian-Frey K, Heinonen K, Marschall V, Merz C, Müller MR, Schröder M, Sykora J, Thiemann M, Fricke H, Gieffers C, Hill O (2019) Abstract 4845: HERA-CD27L, a true CD27 agonist, is a hexavalent CD27 ligand that enhances T cell activation and induces potent anti-tumor immunity. Cancer Res 79(13 Supplement):4845–4845
Segal NH, Logan TF, Hodi FS, McDermott D, Melero I, Hamid O, Schmidt H, Robert C, Chiarion-Sileni V, Ascierto PA, Maio M, Urba WJ, Gangadhar TC, Suryawanshi S, Neely J, Jure-Kunkel M, Krishnan S, Kohrt H, Sznol M, Levy R (2017) Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 23(8):1929–1936
Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ, Cesari R, Chen Y, Davis CB, Huang B, Thall AD, Gopal AK (2018) Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 24(8):1816–1823
Shang Q, Dong Z, Liu C, Bai Y, Guo C, Zhang L, Wang Q (2014) Differential effects of agonistic 4-1BB (CD137) monoclonal antibody on the maturation and functions of hypoxic dendritic cells. Int Immunopharmacol 23(2):609–616
Shapira-Frommer R, Dongen MGV, Dobrenkov K, Chartash E, Liu F, Li C, Wnek R, Patel M (2020) O83 Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. J Immunother Cancer 8(Suppl 1):A2–A2
Sharma RK, Yolcu ES, Shirwan H (2014) SA-4-1BBL as a novel adjuvant for the development of therapeutic cancer vaccines. Expert Rev Vaccines 13(3):387–398
Silence K, Dreier T, Moshir M, Ulrichts P, Gabriels SM, Saunders M, Wajant H, Brouckaert P, Huyghe L, Van Hauwermeiren T, Thibault A, De Haard HJ (2014) ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade. MAbs 6(2):523–532
Snell D, Gunde T, Warmuth S, Lichtlen P, Tietz J, Brock M, Simonin A, Hess C, Christopher W, Heiz R (2020) Preclinical development and mechanism of action studies of NM21-1480, a PD-L1/4-1BB/HSA trispecific MATCH3 therapeutic clinical candidate. AACR
Song N, Li Z, He S, Yang T, Duan Q (2019) Abstract 2397: pre-clinical evaluation of PE0116: a potent cross-linking depednet 4-1BB agonist antibody. Cancer Res 79(13 Supplement):2397–2397
Spira A, Chung K, Patnaik A, Tolcher A, Blaney M, Parikh A, Reddy A, Henner W, McDevitt M, Afar DJAOO (2018) 1149P Safety, tolerability, and pharmacokinetics of the OX40 agonist ABBV-368 in patients with advanced solid tumors. Ann Oncol 29(suppl_8):mdy288. 022
Spriggs MK, Armitage RJ, Strockbine L, Clifford KN, Macduff BM, Sato TA, Maliszewski CR, Fanslow WC (1992) Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med 176(6):1543–1550
Srivastava RM, Trivedi S, Concha-Benavente F, Gibson SP, Reeder C, Ferrone S, Ferris RL (2017) CD137 stimulation enhances cetuximab-induced natural killer: dendritic cell priming of antitumor T-cell immunity in patients with head and neck cancer. Clin Cancer Res 23(3):707–716
Stoll A, Bruns H, Fuchs M, Volkl S, Nimmerjahn F, Kunz M, Peipp M, Mackensen A, Mougiakakos D (2021) CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity. Leukemia
Stone GW, Barzee S, Snarsky V, Santucci C, Tran B, Langer R, Zugates GT, Anderson DG, Kornbluth RS (2009) Nanoparticle-delivered multimeric soluble CD40L DNA combined with Toll-Like Receptor agonists as a treatment for melanoma. PLoS One 4(10):e7334
Sturgill ER, Rolig AS, Linch SN, Mick C, Kasiewicz MJ, Sun Z, Traber PG, Shlevin H, Redmond WL (2021) Galectin-3 inhibition with belapectin combined with anti-OX40 therapy reprograms the tumor microenvironment to favor anti-tumor immunity. Onco Targets Ther 10(1):1892265
Su TT, Gao X, Wang JJCCR (2019) A tumor-localized approach to bypass anti-4-1BB immuno-toxicity. Clin Cancer Res 25(19):5732–5734
Sukumar S, Wilson DC, Yu Y, Wong J, Naravula S, Ermakov G, Riener R, Bhagwat B, Necheva AS, Grein J, Churakova T, Mangadu R, Georgiev P, Manfra D, Pinheiro EM, Sriram V, Bailey WJ, Herzyk D, McClanahan TK, Willingham A, Beebe AM, Sadekova S (2017) Characterization of MK-4166, a clinical agonistic antibody that targets human GITR and inhibits the generation and suppressive effects of T regulatory cells. Cancer Res 77(16):4378–4388
Sum E, Rapp M, Frobel P, Le Clech M, Durr H, Giusti AM, Perro M, Speziale D, Kunz L, Menietti E, Brunker P, Hopfer U, Lechmann M, Sobieniecki A, Appelt B, Adelfio R, Nicolini V, Freimoser-Grundschober A, Jordaan W, Labiano S, Weber F, Emrich T, Christen F, Essig B, Romero P, Trumpfheller C, Umana P (2021) Fibroblast activation protein alpha-targeted CD40 agonism abrogates systemic toxicity and enables administration of High Doses to induce effective antitumor immunity. Clin Cancer Res 27(14):4036–4053
Sun C, He D, Ma C, Gao Z, Chen Y, Wang S (2019) Bifunctional fusion proteins derived from tumstatin and 4-1BBL for targeted cancer therapy. Mol Pharm 16(2):867–876
Sunder-Plassmann R, Pickl WF, Majdic O, Knapp W, Holter W (1995) Crosslinking of CD27 in the presence of CD28 costimulation results in T cell proliferation and cytokine production. Cell Immunol 164(1):20–27
Takahashi C, Mittler RS, Vella AT (2001) Differential clonal expansion of CD4 and CD8 T cells in response to 4-1BB ligation: contribution of 4-1BB during inflammatory responses. Immunol Lett 76(3):183–191
Taraban VY, Rowley TF, Al-Shamkhani A (2004) Cutting edge: a critical role for CD70 in CD8 T cell priming by CD40-licensed APCs. J Immunol 173(11):6542–6546
Taraban VY, Rowley TF, Kerr JP, Willoughby JE, Johnson PM, Al-Shamkhani A, Buchan SL (2013) CD27 costimulation contributes substantially to the expansion of functional memory CD8(+) T cells after peptide immunization. Eur J Immunol 43(12):3314–3323
Teijeira A, Labiano S, Garasa S, Etxeberria I, Santamaría E, Rouzaut A, Enamorado M, Azpilikueta A, Inoges S, Bolaños E, Aznar MA, Sánchez-Paulete AR, Sancho D, Melero I (2018) Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation. Cancer Immunol Res 6(7):798–811
Thiemann M, Richards DM, Heinonen K, Kluge M, Marschall V, Merz C, Redondo Muller M, Schnyder T, Sefrin JP, Sykora J, Fricke H, Gieffers C, Hill O (2018a) A single-chain-based hexavalent CD27 agonist enhances T cell activation and induces anti-tumor immunity. Front Oncol 8:387
Thiemann M, Sykora J, Richards DM, Merz C, Marschall V, Mueller MR, Sefrin JP, Heinonen K, Fricke H, Gieffers C, Hill O (2018b) Abstract 3754: the novel hexavalent human CD137/4-1BB agonist HERA-CD137L promotes anti-cancer immunity by activating CD8 T cells while regulatory T cells are not affected. Cancer Res 78(13 Supplement):3754–3754
Thigpen T (2006) The role of gemcitabine in first-line treatment of advanced ovarian carcinoma. Semin Oncol 33(2 Suppl 6):S26–S32
Tigue NJ, Bamber L, Andrews J, Ireland S, Hair J, Carter E, Sridharan S, Jovanović J, Rees DG, Springall JS, Solier E, Li YM, Chodorge M, Perez-Martinez D, Higazi DR, Oberst M, Kennedy M, Black CM, Yan L, Schwickart M, Maguire S, Cann JA, de Haan L, Young LL, Vaughan T, Wilkinson RW, Stewart R (2017) MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential. Onco Targets Ther 6(3):e1280645
Timmerman J, Herbaux C, Ribrag V, Zelenetz AD, Houot R, Neelapu SS, Logan T, Lossos IS, Urba W, Salles G, Ramchandren R, Jacobson C, Godwin J, Carpio C, Lathers D, Liu Y, Neely J, Suryawanshi S, Koguchi Y, Levy R (2020) Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma. Am J Hematol 95(5):510–520
Tiraboschi C, Gentilini L, Jaworski FM, Corapi E, Velazquez C, Chauchereau A, Laderach DJ, Compagno D (2019) Galectin-3 as a new negative checkpoint of the immune response is the key target for effective immunotherapy against prostate cancer. 763409. https://doi.org/10.1101/763409
Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, Di Gravio D, Huang B, Gambhire D, Chen Y, Thall AD, Pathan N, Schmidt EV, Chow LQM (2017) Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res 23(18):5349–5357
Treilleux I, Blay JY, Bendriss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, Bremond A, Goddard S, Pin JJ, Barthelemy-Dubois C, Lebecque S (2004) Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 10(22):7466–7474
Trüb M, Uhlenbrock F, Claus C, Herzig P, Thelen M, Karanikas V, Bacac M, Amann M, Albrecht R, Ferrara-Koller C, Thommen D, Rothschield S, Savic Prince S, Mertz KD, Cathomas G, Rosenberg R, Heinzelmann-Schwarz V, Wiese M, Lardinois D, Umana P, Klein C, Laubli H, Kashyap AS, Zippelius A (2020) Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. J Immunother Cancer 8(2):e000238
Turaj AH, Hussain K, Cox KL, Rose-Zerilli MJJ, Testa J, Dahal LN, Chan HTC, James S, Field VL, Carter MJ, Kim HJ, West JJ, Thomas LJ, He LZ, Keler T, Johnson PWM, Al-Shamkhani A, Thirdborough SM, Beers SA, Cragg MS, Glennie MJ, Lim SH (2017) Antibody tumor targeting is enhanced by CD27 agonists through myeloid recruitment. Cancer Cell 32(6):777–791.e776
Turaj AH, Cox KL, Penfold CA, French RR, Mockridge CI, Willoughby JE, Tutt AL, Griffiths J, Johnson PWM, Glennie MJ, Levy R, Cragg MS, Lim SH (2018) Augmentation of CD134 (OX40)-dependent NK anti-tumour activity is dependent on antibody cross-linking. Sci Rep 8(1):2278
Turman S, McGlinchey K, Wang Y, Malhotra D, Herbst R, Wang Y (2019) Abstract 1534: MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model. Cancer Res 79(13 Supplement):1534–1534
Urashima M, Chauhan D, Uchiyama H, Freeman GJ, Anderson KC (1995) CD40 ligand triggered interleukin-6 secretion in multiple myeloma. Blood 85(7):1903–1912
Van Audenaerde JR, Marcq E, von Scheidt B, Davey AS, Oliver AJ, De Waele J, Quatannens D, Van Loenhout J, Pauwels P, Roeyen G, Lardon F, Slaney CY, Peeters M, Kershaw MH, Darcy PK, Smits EL (2020) Novel combination immunotherapy for pancreatic cancer: potent anti-tumor effects with CD40 agonist and interleukin-15 treatment. Clin Transl Immunol 9(8):e1165
Van Deusen KE, Rajapakse R, Bullock TN (2010) CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4+ T cell-dependent, licensed CD8+ T cell responses. J Leukoc Biol 87(3):477–485
van Hooren L, Vaccaro A, Ramachandran M, Vazaios K, Libard S, van de Walle T, Georganaki M, Huang H, Pietila I, Lau J, Ulvmar MH, Karlsson MCI, Zetterling M, Mangsbo SM, Jakola AS, Olsson Bontell T, Smits A, Essand M, Dimberg A (2021) Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. Nat Commun 12(1):4127
Vanichakarn P, Blair P, Wu C, Freedman JE, Chakrabarti S (2008) Neutrophil CD40 enhances platelet-mediated inflammation. Thromb Res 122(3):346–358
Vidard L, Dureuil C, Baudhuin J, Vescovi L, Durand L, Sierra V, Parmantier E (2019) CD137 (4-1BB) engagement fine-tunes synergistic IL-15- and IL-21-driven NK cell proliferation. J Immunol 203(3):676–685
Vitale LA, Thomas LJ (2019) Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy. Cancer Immunol Immunother 68(2):233–245
Vitale LA, He LZ, Thomas LJ, Widger J, Weidlick J, Crocker A, O’Neill T, Storey J, Glennie MJ, Grote DM, Ansell SM, Marsh H, Keler T (2012) Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clin Cancer Res 18(14):3812–3821
Vitale LA, Thomas LJ, O’Neill T, Widger J, Mills-Chen L, Crocker A, Patterson C, Wasiuk A, Forsberg E, Boyer J, Sisson C, Weidlick J, Renn-Bingham S, Papayannopoulos I, Hammond R, Goldstein J, Marsh HC, Keler T, He L-Z (2019) Abstract 2392: CDX-527: a novel bispecific immune-modulating antibody targeting CD27 and PD-L1. Cancer Res 79(13 Supplement):2392–2392
Vitale LA, He LZ, Thomas LJ, Wasiuk A, O’Neill T, Widger J, Crocker A, Mills-Chen L, Forsberg E, Weidlick J, Patterson C, Hammond RA, Boyer J, Sisson C, Alvarado D, Goldstein J, Marsh HC Jr, Keler T (2020) Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy. Cancer Immunol Immunother
Vonderheide RH, Dutcher JP, Anderson JE, Eckhardt SG, Stephans KF, Razvillas B, Garl S, Butine MD, Perry VP, Armitage RJ, Ghalie R, Caron DA, Gribben JG (2001) Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 19(13):3280–3287
Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Li XC (2007) OX40 costimulation turns off Foxp3+ Tregs. Blood 110(7):2501–2510
Wajant H (2015) Principles of antibody-mediated TNF receptor activation. Cell Death Differ 22(11):1727–1741
Wajant H, Siegmund D (2019) TNFR1 and TNFR2 in the control of the life and death balance of macrophages. Front Cell Dev Biol 7:91
Waldmann TA, Dubois S, Miljkovic MD, Conlon KC (2020a) IL-15 in the combination immunotherapy of cancer. Front Immunol 11:868
Waldmann TA, Miljkovic MD, Conlon KC (2020b) Interleukin-15 (dys)regulation of lymphoid homeostasis: implications for therapy of autoimmunity and cancer. J Exp Med 217(1)
Wang B, Zhang W, Jankovic V, Golubov J, Poon P, Oswald EM, Gurer C, Wei J, Ramos I, Wu Q, Waite J, Ni M, Adler C, Wei Y, Macdonald L, Rowlands T, Brydges S, Siao J, Poueymirou W, MacDonald D, Yancopoulos GD, Sleeman MA, Murphy AJ, Skokos D (2018a) Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8(+) T cell dysfunction and maintain memory phenotype. Sci Immunol 3(29)
Wang R, Feng Y, Hilt E, Yuan X, Gao C, Shao X, Sun Y, D’silva M, Yang K, Penhallow B (2018b) Abstract LB-127: from bench to bedside: exploring OX40 receptor modulation in a phase 1/2a study of the OX40 costimulatory agonist BMS-986178±nivolumab (NIVO) or ipilimumab (IPI) in patients with advanced solid tumors. AACR
Wang R, Gao C, Raymond M, Dito G, Kabbabe D, Shao X, Hilt E, Sun Y, Pak I, Gutierrez M, Melero I, Spreafico A, Carvajal RD, Ong M, Olszanski AJ, Milburn C, Thudium K, Yang Z, Feng Y, Fracasso PM, Korman AJ, Aanur P, Huang SA, Quigley M (2019) An integrative approach to inform optimal administration of OX40 agonist antibodies in patients with advanced solid tumors. Clin Cancer Res 25(22):6709–6720
Wang F, Chau B, West SM, Kimberlin CR, Cao F, Schwarz F, Aguilar B, Han M, Morishige W, Bee C, Dollinger G, Rajpal A, Strop P (2021) Structures of mouse and human GITR-GITRL complexes reveal unique TNF superfamily interactions. Nat Commun 12(1):1378
Wasiuk A, Weidlick J, Sisson C, Widger J, Crocker A, Vitale L, Marsh HC, Keler T, He LZ (2021) Conditioning treatment with CD27 Ab enhances expansion and antitumor activity of adoptively transferred T cells in mice. Cancer Immunol Immunother
Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68
Weatherill AR, Maxwell JR, Takahashi C, Weinberg AD, Vella AT (2001) OX40 ligation enhances cell cycle turnover of Ag-activated CD4 T cells in vivo. Cell Immunol 209(1):63–75
Weinberg AD, Vella AT, Croft M (1998) OX-40: life beyond the effector T cell stage. Semin Immunol 10(6):471–480
Weinberg AD, Wegmann KW, Funatake C, Whitham RH (1999) Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. J Immunol 162(3):1818–1826
Weinberg AD, Rivera MM, Prell R, Morris A, Ramstad T, Vetto JT, Urba WJ, Alvord G, Bunce C, Shields J (2000) Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 164(4):2160–2169
Wen T, Bukczynski J, Watts TH (2002) 4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function. J Immunol 168(10):4897–4906
White AL, Chan HT, French RR, Willoughby J, Mockridge CI, Roghanian A, Penfold CA, Booth SG, Dodhy A, Polak ME, Potter EA, Ardern-Jones MR, Verbeek JS, Johnson PW, Al-Shamkhani A, Cragg MS, Beers SA, Glennie MJ (2015) Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies. Cancer Cell 27(1):138–148
Wiehagen KR, Girgis NM, Yamada DH, Smith AA, Chan SR, Grewal IS, Quigley M, Verona RI (2017) Combination of CD40 agonism and CSF-1R blockade reconditions tumor-associated macrophages and drives potent antitumor immunity. Cancer Immunol Res 5(12):1109–1121
Wood KW, Gartner EM, Jonas M, Ryan M, Kennedy DA (2015) Abstract 1686: CD70 as a target in non-Hodgkin lymphoma (NHL) and renal cell carcinoma (RCC). Cancer Res 75(15 Supplement):1686–1686
Wouters MC, Komdeur FL, Workel HH, Klip HG, Plat A, Kooi NM, Wisman GB, Mourits MJ, Arts HJ, Oonk MH, Yigit R, de Jong S, Melief CJ, Hollema H, Duiker EW, Daemen T, de Bruyn M, Nijman HW (2016) Treatment regimen, surgical outcome, and T-cell differentiation influence prognostic benefit of tumor-infiltrating lymphocytes in high-grade serous ovarian cancer. Clin Cancer Res 22(3):714–724
Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455
Wyzgol A, Muller N, Fick A, Munkel S, Grigoleit GU, Pfizenmaier K, Wajant H (2009) Trimer stabilization, oligomerization, and antibody-mediated cell surface immobilization improve the activity of soluble trimers of CD27L, CD40L, 41BBL, and glucocorticoid-induced TNF receptor ligand. J Immunol 183(3):1851–1861
Xiao Y, Peperzak V, Keller AM, Borst J (2008) CD27 instructs CD4+ T cells to provide help for the memory CD8+ T cell response after protein immunization. J Immunol 181(2):1071–1082
Xiao X, Gong W, Demirci G, Liu W, Spoerl S, Chu X, Bishop DK, Turka LA, Li XC (2012) New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol 188(2):892–901
Xiao X, Shi X, Fan Y, Zhang X, Wu M, Lan P, Minze L, Fu YX, Ghobrial RM, Liu W, Li XC (2015) GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation. Nat Commun 6:8266
Xu DP, Sauter BV, Huang TG, Meseck M, Woo SL, Chen SH (2005) The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma. Gene Ther 12(20):1526–1533
Yachnin J, Ullenhag GJ, Carneiro A, Nielsen D, Rohrberg KS, Kvarnhammar AM, Schultz L, Bågeman E, Wennersten C, Russell CA (2020) A first-in-human phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of ATOR-1015, a CTLA-4 x OX40 bispecific antibody. J Clin Oncol 38(15_suppl):3061–3061
Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (2007) CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood 110(7):2537–2544
Yang F, He Z, Duan H, Zhang D, Li J, Yang H, Dorsey JF, Zou W, Nabavizadeh SA, Bagley SJ, Abdullah K, Brem S, Zhang L, Xu X, Byrne KT, Vonderheide RH, Gong Y, Fan Y (2021) Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40. Nat Commun 12(1):3424
Ye S, Cohen D, Belmar NA, Choi D, Tan SS, Sho M, Akamatsu Y, Kim H, Iyer R, Cabel J, Lake M, Song D, Harlan J, Zhang C, Fang Y, Wahl AF, Culp P, Hollenbaugh D, Chao DT (2019) A bispecific molecule targeting CD40 and tumor antigen mesothelin enhances tumor-specific immunity. Cancer Immunol Res 7(11):1864–1875
You G, Lee Y, Kang YW, Park HW, Park K, Kim H, Kim YM, Kim S, Kim JH, Moon D, Chung H, Son W, Jung UJ, Park E, Lee S, Son YG, Eom J, Won J, Park Y, Jung J, Lee SW (2021) B7-H3x4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8(+) tumor-infiltrating lymphocytes. Sci Adv 7(3)
Zaini J, Andarini S, Tahara M, Saijo Y, Ishii N, Kawakami K, Taniguchi M, Sugamura K, Nukiwa T, Kikuchi T (2007) OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice. J Clin Invest 117(11):3330–3338
Zapata JM, Perez-Chacon G, Carr-Baena P, Martinez-Forero I, Azpilikueta A, Otano I, Melero I (2018) CD137 (4-1BB) signalosome: complexity is a Matter of TRAFs. Front Immunol 9:2618
Zappasodi R, Sirard C, Li Y, Budhu S, Abu-Akeel M, Liu C, Yang X, Zhong H, Newman W, Qi J, Wong P, Schaer D, Koon H, Velcheti V, Hellmann MD, Postow MA, Callahan MK, Wolchok JD, Merghoub T (2019) Rational design of anti-GITR-based combination immunotherapy. Nat Med 25(5):759–766
Zhang X, Xiao X, Lan P, Li J, Dou Y, Chen W, Ishii N, Chen S, Xia B, Chen K, Taparowsky E, Li XC (2018) OX40 Costimulation inhibits Foxp3 expression and Treg induction via BATF3-dependent and independent mechanisms. Cell Rep 24(3):607–618
Zhang X, Wang Y, Zhang D, Li H, Zhou Z, Yang R (2020) CD70-silenced dendritic cells induce immune tolerance in immune thrombocytopenia patients. Br J Haematol 191(3):466–475
Zheng G, Wang B, Chen A (2004) The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells. J Immunol 173(4):2428–2434
Zhou SN, Ran RZ, Tan LL, Guo H (2018) Current perspectives of SA-4-1BBL in immune modulation during cancer. Exp Ther Med 15(3):2699–2702
Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74(18):5057–5069
Zhu MMT, Burugu S, Gao D, Yu J, Kos Z, Leung S, Horst BA, Nielsen TO (2020) Evaluation of glucocorticoid-induced TNF receptor (GITR) expression in breast cancer and across multiple tumor types. Mod Pathol 33:1753–1763
Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL (2004) Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions. J Immunol 173(6):3716–3724
Zou W, Machelon V, Coulomb-L’Hermin A, Borvak J, Nome F, Isaeva T, Wei S, Krzysiek R, Durand-Gasselin I, Gordon A, Pustilnik T, Curiel DT, Galanaud P, Capron F, Emilie D, Curiel TJ (2001) Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 7(12):1339–1346
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Vlaming, M., He, Y., Bremer, E. (2023). Advances in Therapeutic Targeting of the Tumor Necrosis Factor Receptor Superfamily Members for Cancer Immunotherapy. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_196-1
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