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Parallel Costimulation of Effector and Regulatory T Cells by OX40, GITR, TNFRSF25, CD27, and CD137: Implications for Cancer Immunotherapy

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Novel Immunotherapeutic Approaches to the Treatment of Cancer

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Abstract

Adaptive immune responses are triggered by antigen presenting cells that display particular antigens in the context of MHC molecules and in the presence of appropriate costimulatory molecules. These costimulatory molecules are diverse, and include members of the Immunoglobulin (Ig) and TNF receptor superfamilies. In general, costimulatory molecules are induced by innate immune stimuli and their expression is transient, signaling the presence of a potential threat. The presence of costimulatory molecules is critical to overcome the predominance of inhibitory immune signals needed to initiate an adaptive immune response. TNF receptor superfamily molecules are particularly important for the fine-tuning of adaptive immune responses, and often have dual effects toward both effector and regulatory T cells. Five of the better studied effector T cell costimulators: 4-1BB, GITR, OX40, TNFRSF25, and CD27, can all augment effector and regulatory T cell biology in unique ways. An understanding of how these pathways are similar, and where they diverge, may facilitate the clinical development of receptor agonists for use in cancer immunotherapy.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

APC:

Antigen presenting cell

DR3:

Death receptor 3

EAE:

Experimental autoimmune encephalomyelitis

Ig:

Immunoglobulin

TCR:

T cell receptor

Teff:

Effector T cell

Treg:

Regulatory T cells

References

  • Akiba, H., Oshima, H., Takeda, K., Atsuta, M., Nakano, H., Nakajima, A., et al.: CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B cells. J. Immunol. 162, 7058–7066 (1999)

    CAS  PubMed  Google Scholar 

  • Arens, R., Tesselaar, K., Baars, P.A., van Schijndel, G.M., Hendriks, J., Pals, S.T., et al.: Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion. Immunity 15, 801–812 (2001)

    Article  CAS  PubMed  Google Scholar 

  • Ashkenazi, A., Dixit, V.M.: Death receptors: signaling and modulation. Science 281, 1305–1308 (1998)

    Article  CAS  PubMed  Google Scholar 

  • Bamias, G., Mishina, M., Nyce, M., Ross, W.G., Kollias, G., Rivera-Nieves, J., et al.: Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc. Natl. Acad. Sci. U. S. A. 103, 8441–8446 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bigler, R.D., Bushkin, Y., Chiorazzi, N.: S152 (CD27). A modulating disulfide-linked T cell activation antigen. J. Immunol. 141, 21–28 (1988)

    CAS  PubMed  Google Scholar 

  • Bodmer, J.L., Burns, K., Schneider, P., Hofmann, K., Steiner, V., Thome, M., et al.: TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). Immunity 6, 79–88 (1997)

    Article  CAS  PubMed  Google Scholar 

  • Bodmer, J.L., Schneider, P., Tschopp, J.: The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Borst, J., Hendriks, J., Xiao, Y.: CD27 and CD70 in T cell and B cell activation. Curr. Opin. Immunol. 17, 275–281 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Bull, M.J., Williams, A.S., Mecklenburgh, Z., Calder, C.J., Twohig, J.P., Elford, C., et al.: The death receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. J. Exp. Med. 205, 2457–2464 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bulliard, Y., Jolicoeur, R., Zhang, J., Dranoff, G., Wilson, N.S., Brogdon, J.L.: OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy. Immunol. Cell Biol. 92, 475–480 (2014)

    Article  CAS  PubMed  Google Scholar 

  • Calderhead, D.M., Buhlmann, J.E., van den Eertwegh, A.J., Claassen, E., Noelle, R.J., Fell, H.P.: Cloning of mouse Ox40: a T cell activation marker that may mediate T-B cell interactions. J. Immunol. 151, 5261–5271 (1993)

    CAS  PubMed  Google Scholar 

  • Chinnaiyan, A.M., O’Rourke, K., Yu, G.L., Lyons, R.H., Garg, M., Duan, D.R., et al.: Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science 274, 990–992 (1996)

    Article  CAS  PubMed  Google Scholar 

  • Claus, C., Riether, C., Schurch, C., Matter, M.S., Hilmenyuk, T., Ochsenbein, A.F.: CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res. 72, 3664–3676 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Cohen, A.D., Schaer, D.A., Liu, C., Li, Y., Hirschhorn-Cymmerman, D., Kim, S.C., et al.: Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One 5, e10436 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Coquet, J.M., Ribot, J.C., Babala, N., Middendorp, S., van der Horst, G., Xiao, Y., et al.: Epithelial and dendritic cells in the thymic medulla promote CD4 + Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med. 210, 715–728 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Croft, M.: Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Curran, M.A., Kim, M., Montalvo, W., Al-Shamkhani, A., Allison, J.P.: Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One 6, e19499 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curti, B.D., Kovacsovics-Bankowski, M., Morris, N., Walker, E., Chisholm, L., Floyd, K., et al.: OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189–7198 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Goer de Herve, M.G., Jaafoura, S., Vallee, M., Taoufik, Y.: FoxP3(+) regulatory CD4 T cells control the generation of functional CD8 memory. Nat. Commun. 3, 986 (2012)

    Article  CAS  Google Scholar 

  • Dong, H., Franklin, N.A., Roberts, D.J., Yagita, H., Glennie, M.J., Bullock, T.N.: CD27 stimulation promotes the frequency of IL-7 receptor-expressing memory precursors and prevents IL-12-mediated loss of CD8(+) T cell memory in the absence of CD4(+) T cell help. J. Immunol. 188, 3829–3838 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan, W., So, T., Croft, M.: Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting OX40L and suppressing antigen-specific Foxp3+ T regulatory cells. J. Immunol. 181, 8650–8659 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elpek, K.G., Yolcu, E.S., Franke, D.D., Lacelle, C., Schabowsky, R.H., Shirwan, H.: Ex vivo expansion of CD4 + CD25 + FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling. J. Immunol. 179, 7295–7304 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Ephrem, A., Epstein, A.L., Stephens, G.L., Thornton, A.M., Glass, D., Shevach, E.M.: Modulation of Treg cells/T effector function by GITR signaling is context-dependent. Eur. J. Immunol. 43, 2421–2429 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Fang, L., Adkins, B., Deyev, V., Podack, E.R.: Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J. Exp. Med. 205, 1037–1048 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foell, J., Strahotin, S., O’Neil, S.P., McCausland, M.M., Suwyn, C., Haber, M., et al.: CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J. Clin. Invest. 111, 1505–1518 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaspal, F., Withers, D., Saini, M., Bekiaris, V., McConnell, F.M., White, A., et al.: Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice. J. Exp. Med. 208, 1579–1584 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Gavin, M.A., Clarke, S.R., Negrou, E., Gallegos, A., Rudensky, A.: Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat. Immunol. 3, 33–41 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Godfrey, W.R., Fagnoni, F.F., Harara, M.A., Buck, D., Engleman, E.G.: Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor. J. Exp. Med. 180, 757–762 (1994)

    Article  CAS  PubMed  Google Scholar 

  • Gopisetty, A., Bhattacharya, P., Haddad, C., Bruno Jr., J.C., Vasu, C., Miele, L., et al.: OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells. J. Immunol. 190, 5516–5525 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham, J.B., Da Costa, A., Lund, J.M.: Regulatory T cells shape the resident memory T cell response to virus infection in the tissues. J. Immunol. 192, 683–690 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gramaglia, I., Weinberg, A.D., Lemon, M., Croft, M.: Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J. Immunol. 161, 6510–6517 (1998)

    CAS  PubMed  Google Scholar 

  • Gravestein, L.A., Nieland, J.D., Kruisbeek, A.M., Borst, J.: Novel mAbs reveal potent co-stimulatory activity of murine CD27. Int. Immunol. 7, 551–557 (1995)

    Article  CAS  PubMed  Google Scholar 

  • Griseri, T., Asquith, M., Thompson, C., Powrie, F.: OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699–709 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo, Z., Cheng, D., Xia, Z., Luan, M., Wu, L., Wang, G., et al.: Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer. J. Transl. Med. 11, 215 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He, L.Z., Prostak, N., Thomas, L.J., Vitale, L., Weidlick, J., Crocker, A., et al.: Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice. J. Immunol. 191, 4174–4183 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Hendriks, J., Xiao, Y., Borst, J.: CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J. Exp. Med. 198, 1369–1380 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirschhorn-Cymerman, D., Rizzuto, G.A., Merghoub, T., Cohen, A.D., Avogadri, F., Lesokhin, A.M., et al.: OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J. Exp. Med. 206, 1103–1116 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu, P., Arias, R.S., Sadun, R.E., Nien, Y.C., Zhang, N., Sabzevari, H., et al.: Construction and preclinical characterization of Fc-mGITRL for the immunotherapy of cancer. Clin. Cancer Res. 14, 579–588 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Jin, T., Kim, S., Guo, F., Howard, A., Zhang, Y.Z.: Purification and crystallization of recombinant human TNF-like ligand TL1A. Cytokine 40, 115–122 (2007a)

    Article  CAS  PubMed  Google Scholar 

  • Jin, T., Guo, F., Kim, S., Howard, A., Zhang, Y.Z.: X-ray crystal structure of TNF ligand family member TL1A at 2.1A. Biochem. Biophys. Res. Commun. 364, 1–6 (2007b)

    Article  CAS  PubMed  Google Scholar 

  • Keller, A.M., Schildknecht, A., Xiao, Y., van den Broek, M., Borst, J.: Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity 29, 934–946 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Khan, S.Q., Tsai, M.S., Schreiber, T.H., Wolf, D., Deyev, V.V., Podack, E.R.: Cloning, expression, and functional characterization of TL1A-Ig. J. Immunol. 190, 1540–1550 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Kitson, J., Raven, T., Jiang, Y.P., Goeddel, D.V., Giles, K.M., Pun, K.T., et al.: A death-domain-containing receptor that mediates apoptosis. Nature 384, 372–375 (1996)

    Article  CAS  PubMed  Google Scholar 

  • Kjaergaard, J., Tanaka, J., Kim, J.A., Rothchild, K., Weinberg, A., Shu, S.: Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth. Cancer Res. 60, 5514–5521 (2000)

    CAS  PubMed  Google Scholar 

  • Ko, K., Yamazaki, S., Nakamura, K., Nishioka, T., Hirota, K., Yamaguchi, T., et al.: 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, 885–891 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohm, A.P., Williams, J.S., Miller, S.D.: Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis. J. Immunol. 172, 4686–4690 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Kohrt, H.E., Colevas, A.D., Houot, R., Weiskopf, K., Goldstein, M.J., Lund, P., et al.: Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668–2682 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kroemer, A., Xiao, X., Vu, M.D., Gao, W., Minamimura, K., Chen, M., et al.: OX40 controls functionally different T cell subsets and their resistance to depletion therapy. J. Immunol. 179, 5584–5591 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Kwon, B.S., Weissman, S.M.: cDNA sequences of two inducible T-cell genes. Proc. Natl. Acad. Sci. U. S. A. 86, 1963–1967 (1989)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laidlaw, B.J., Cui, W., Amezquita, R.A., Gray, S.M., Guan, T., Lu, Y., et al.: Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat. Immunol. 16, 871–879 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, S.W., Salek-Ardakani, S., Mittler, R.S., Croft, M.: Hypercostimulation through 4-1BB distorts homeostasis of immune cells. J. Immunol. 182, 6753–6762 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao, G., Nayak, S., Regueiro, J.R., Berger, S.B., Detre, C., Romero, X., et al.: GITR engagement preferentially enhances proliferation of functionally competent CD4 + CD25 + FoxP3+ regulatory T cells. Int. Immunol. 22, 259–270 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mack, D.G., Lanham, A.M., Palmer, B.E., Maier, L.A., Fontenot, A.P.: CD27 expression on CD4+ T cells differentiates effector from regulatory T cell subsets in the lung. J. Immunol. 182, 7317–7324 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahoney, K.M., Rennert, P.D., Freeman, G.J.: Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561–584 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Mallett, S., Fossum, S., Barclay, A.N.: Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes--a molecule related to nerve growth factor receptor. EMBO J. 9, 1063–1068 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marsters, S.A., Sheridan, J.P., Donahue, C.J., Pitti, R.M., Gray, C.L., Goddard, A.D., et al.: Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B. Curr. Biol.. 6, 1669–1676 (1996)

    Article  CAS  PubMed  Google Scholar 

  • McHugh, R.S., Whitters, M.J., Piccirillo, C.A., Young, D.A., Shevach, E.M., Collins, M., et al.: CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002)

    Article  CAS  PubMed  Google Scholar 

  • McMillin, D.W., Hewes, B., Gangadharan, B., Archer, D.R., Mittler, R.S., Spencer, H.T.: Complete regression of large solid tumors using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy. Hum. Gene Ther. 17, 798–806 (2006)

    Article  CAS  PubMed  Google Scholar 

  • Melero, I., Shuford, W.W., Newby, S.A., Aruffo, A., Ledbetter, J.A., Hellstrom, K.E., et al.: Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med. 3, 682–685 (1997)

    Article  CAS  PubMed  Google Scholar 

  • Melero, I., Murillo, O., Dubrot, J., Hervas-Stubbs, S., Perez-Gracia, J.L.: Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies. Trends Pharmacol. Sci. 29, 383–390 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Melero, I., Hirschhorn-Cymerman, D., Morales-Kastresana, A., Sanmamed, M.F., Wolchok, J.D.: Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin. Cancer Res. 19, 1044–1053 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meylan, F., Davidson, T.S., Kahle, E., Kinder, M., Acharya, K., Jankovic, D., et al.: The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 29, 79–89 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meylan, F., Song, Y.J., Fuss, I., Villarreal, S., Kahle, E., Malm, I.J., et al.: The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal immunol. 4, 172–185 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Migone, T.S., Zhang, J., Luo, X., Zhuang, L., Chen, C., Hu, B., et al.: TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16, 479–492 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Nam, K.O., Kang, W.J., Kwon, B.S., Kim, S.J., Lee, H.W.: The therapeutic potential of 4-1BB (CD137) in cancer. Curr. Cancer Drug Targets 5, 357–363 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Niu, L., Strahotin, S., Hewes, B., Zhang, B., Zhang, Y., Archer, D., et al.: Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J. Immunol. 178, 4194–4213 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pace, L., Tempez, A., Arnold-Schrauf, C., Lemaitre, F., Bousso, P., Fetler, L., et al.: Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 338, 532–536 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Pappu, B.P., Borodovsky, A., Zheng, T.S., Yang, X., Wu, P., Dong, X., et al.: TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J. Exp. Med. 205, 1049–1062 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ray, A., Basu, S., Williams, C.B., Salzman, N.H., Dittel, B.N.: A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J. Immunol. 188, 3188–3198 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redmond, W.L., Linch, S.N., Kasiewicz, M.J.: Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immun. Res. 2, 142–153 (2014)

    Article  CAS  Google Scholar 

  • Riether, C., Schurch, C., Ochsenbein, A.F.: Modulating CD27 signaling to treat cancer. Oncoimmunology 1, 1604–1606 (2012)

    Article  PubMed  PubMed Central  Google Scholar 

  • Roberts, D.J., Franklin, N.A., Kingeter, L.M., Yagita, H., Tutt, A.L., Glennie, M.J., et al.: 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, 769–779 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruby, C.E., Redmond, W.L., Haley, D., Weinberg, A.D.: Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur. J. Immunol. 37, 157–166 (2007)

    Article  CAS  PubMed  Google Scholar 

  • Schaer, D.A., Budhu, S., Liu, C., Bryson, C., Malandro, N., Cohen, A., et al.: GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immun. Res. 1, 320–331 (2013)

    Article  CAS  Google Scholar 

  • Schreiber, T.H., Podack, E.R.: Immunobiology of TNFSF15 and TNFRSF25. Immunol. Res. 57, 3–11 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Schreiber, T.H., Wolf, D., Tsai, M.S., Chirinos, J., Deyev, V.V., Gonzalez, L., et al.: Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. J. Clin. Invest. 120, 3629–3640 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schreiber, T.H., Wolf, D., Podack, E.R.: The role of TNFRSF25:TNFSF15 in disease… health? Adv. Exp. Med. Biol. 691, 289–298 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Schreiber, T.H., Wolf, D., Bodero, M., Gonzalez, L., Podack, E.R.: T cell costimulation by TNFR superfamily (TNFRSF)4 and TNFRSF25 in the context of vaccination. J. Immunol. 189, 3311–3318 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Screaton, G.R., Xu, X.N., Olsen, A.L., Cowper, A.E., Tan, R., McMichael, A.J., et al.: LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. Proc. Natl. Acad. Sci. U. S. A. 94, 4615–4619 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seo, S.K., Choi, J.H., Kim, Y.H., Kang, W.J., Park, H.Y., Suh, J.H., et al.: 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med. 10, 1088–1094 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Shi, W., Siemann, D.W.: Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res. 26, 3445–3453 (2006)

    CAS  PubMed  Google Scholar 

  • Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., Sakaguchi, S.: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002)

    Article  CAS  PubMed  Google Scholar 

  • Slebioda, T.J., Rowley, T.F., Ferdinand, J.R., Willoughby, J.E., Buchan, S.L., Taraban, V.Y., et al.: Triggering of TNFRSF25 promotes CD8(+) T-cell responses and anti-tumor immunity. Eur. J. Immunol. 41, 2606–2611 (2011)

    Article  CAS  PubMed  Google Scholar 

  • Snell, L.M., McPherson, A.J., Lin, G.H., Sakaguchi, S., Pandolfi, P.P., Riccardi, C., et al.: CD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection. J. Immunol. 185, 7223–7234 (2010)

    Article  CAS  PubMed  Google Scholar 

  • So, T., Croft, M.: Cutting edge: OX40 inhibits TGF-beta- and antigen-driven conversion of naive CD4 T cells into CD25+Foxp3+ T cells. J. Immunol. 179, 1427–1430 (2007)

    Article  CAS  PubMed  Google Scholar 

  • So, T., Lee, S.W., Croft, M.: Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine Growth Factor Rev. 19, 253–262 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song, J., Salek-Ardakani, S., Rogers, P.R., Cheng, M., Van Parijs, L., Croft, M.: The costimulation-regulated duration of PKB activation controls T cell longevity. Nat. Immunol. 5, 150–158 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Starck, L., Scholz, C., Dorken, B., Daniel, P.T.: Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIP(short) via phosphatidylinositol 3-kinase and AKT/protein kinase B. Eur. J. Immunol. 35, 1257–1266 (2005)

    Article  PubMed  CAS  Google Scholar 

  • Stephens, G.L., McHugh, R.S., Whitters, M.J., Young, D.A., Luxenberg, D., Carreno, B.M., et al.: Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J. Immunol. 173, 5008–5020 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Sun, Y., Chen, H.M., Subudhi, S.K., Chen, J., Koka, R., Chen, L., et al.: Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat. Med. 8, 1405–1413 (2002a)

    Article  CAS  PubMed  Google Scholar 

  • Sun, Y., Lin, X., Chen, H.M., Wu, Q., Subudhi, S.K., Chen, L., et al.: Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis. J. Immunol. 168, 1457–1465 (2002b)

    Article  CAS  PubMed  Google Scholar 

  • Takeda, K., Oshima, H., Hayakawa, Y., Akiba, H., Atsuta, M., Kobata, T., et al.: CD27-mediated activation of murine NK cells. J. Immunol. 164, 1741–1745 (2000)

    Article  CAS  PubMed  Google Scholar 

  • Takeda, I., Ine, S., Killeen, N., Ndhlovu, L.C., Murata, K., Satomi, S., et al.: Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J. Immunol. 172, 3580–3589 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Takeda, K., Kojima, Y., Uno, T., Hayakawa, Y., Teng, M.W., Yoshizawa, H., et al.: Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J. Immunol. 184, 5493–5501 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Taraban, V.Y., Slebioda, T.J., Willoughby, J.E., Buchan, S.L., James, S., Sheth, B., et al.: Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia. Mucosal immunol. 4, 186–196 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tesselaar, K., Xiao, Y., Arens, R., van Schijndel, G.M., Schuurhuis, D.H., Mebius, R.E., et al.: Expression of the murine CD27 ligand CD70 in vitro and in vivo. J. Immunol. 170, 33–40 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Thomas, L.J., He, L.Z., Marsh, H., Keler, T.: Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity. Oncoimmunology 3, e27255 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  • Uno, T., Takeda, K., Kojima, Y., Yoshizawa, H., Akiba, H., Mittler, R.S., et al.: Eradication of established tumors in mice by a combination antibody-based therapy. Nat. Med. 12, 693–698 (2006)

    Article  CAS  PubMed  Google Scholar 

  • van Lier, R.A., Borst, J., Vroom, T.M., Klein, H., Van Mourik, P., Zeijlemaker, W.P., et al.: Tissue distribution and biochemical and functional properties of Tp55 (CD27), a novel T cell differentiation antigen. J. Immunol. 139, 1589–1596 (1987)

    PubMed  Google Scholar 

  • van Olffen, R.W., Koning, N., van Gisbergen, K.P., Wensveen, F.M., Hoek, R.M., Boon, L., et al.: GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo. J. Immunol. 182, 7490–7500 (2009)

    Article  PubMed  CAS  Google Scholar 

  • Vinay, D.S., Kwon, B.S.: Role of 4-1BB in immune responses. Semin. Immunol. 10, 481–489 (1998)

    Article  CAS  PubMed  Google Scholar 

  • Vinay, D.S., Kwon, B.S.: Immunotherapy of cancer with 4-1BB. Mol. Cancer Ther. 11, 1062–1070 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Vitale, L.A., He, L.Z., Thomas, L.J., Widger, J., Weidlick, J., Crocker, A., et al.: Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clin. Cancer Res. 18, 3812–3821 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Voo, K.S., Bover, L., Harline, M.L., Vien, L.T., Facchinetti, V., Arima, K., et al.: Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J. Immunol. 191, 3641–3650 (2013)

    Article  CAS  PubMed  Google Scholar 

  • Vu, M.D., Xiao, X., Gao, W., Degauque, N., Chen, M., Kroemer, A., et al.: OX40 costimulation turns off Foxp3+ Tregs. Blood 110, 2501–2510 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warzocha, K., Salles, G.: The tumor necrosis factor signaling complex: choosing a path toward cell death or cell proliferation. Leukemia & lymphoma. 29, 81–92 (1998)

    Article  CAS  Google Scholar 

  • Watts, T.H.: TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005)

    Article  CAS  PubMed  Google Scholar 

  • Weinberg, A.D., Bourdette, D.N., Sullivan, T.J., Lemon, M., Wallin, J.J., Maziarz, R., et al.: Selective depletion of myelin-reactive T cells with the anti-OX-40 antibody ameliorates autoimmune encephalomyelitis. Nat. Med. 2, 183–189 (1996)

    Article  CAS  PubMed  Google Scholar 

  • Weinberg, A.D., Wegmann, K.W., Funatake, C., Whitham, R.H.: 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, 1818–1826 (1999)

    CAS  PubMed  Google Scholar 

  • Weinberg, A.D., Rivera, M.M., Prell, R., Morris, A., Ramstad, T., Vetto, J.T., et al.: Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J. Immunol. 164, 2160–2169 (2000)

    Article  CAS  PubMed  Google Scholar 

  • Wen, L., Zhuang, L., Luo, X., Wei, P.: TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells. J. Biol. Chem. 278, 39251–39258 (2003)

    Article  CAS  PubMed  Google Scholar 

  • Wolf, D., Schreiber, T.H., Tryphonopoulos, P., Li, S., Tzakis, A.G., Ruiz, P., et al.: Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival. Transplantation 94, 569–574 (2012)

    Article  CAS  PubMed  Google Scholar 

  • Xiao, X., Kroemer, A., Gao, W., Ishii, N., Demirci, G., Li, X.C.: OX40/OX40L costimulation affects induction of Foxp3+ regulatory T cells in part by expanding memory T cells in vivo. J. Immunol. 181, 3193–3201 (2008)

    Article  CAS  PubMed  Google Scholar 

  • Xiao, X., Gong, W., Demirci, G., Liu, W., Spoerl, S., Chu, X., et al.: New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J. Immunol. 188, 892–901 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yonezawa, A., Dutt, S., Chester, C., Kim, J., Kohrt, H.E.: Boosting cancer immunotherapy with anti-CD137 antibody therapy. Clin. Cancer Res. 21, 3113–3120 (2015)

    Article  CAS  PubMed  Google Scholar 

  • Zheng, G., Wang, B., Chen, A.: The 4-1BB costimulation augments the proliferation of CD4 + CD25+ regulatory T cells. J. Immunol. 173, 2428–2434 (2004)

    Article  CAS  PubMed  Google Scholar 

  • Zhou, P., L’Italien, L., Hodges, D., Schebye, X.M.: Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J. Immunol. 179, 7365–7375 (2007)

    Article  CAS  PubMed  Google Scholar 

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  1. Heat Biologics, Inc., Durham, North Carolina, USA

    Taylor H. Schreiber

  2. Pelican Therapeutics, Inc., Durham, North Carolina, USA

    Taylor H. Schreiber

  3. The University of Miami, Coral Gables, FL, USA

    Taylor H. Schreiber

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    Paul D. Rennert

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Schreiber, T.H. (2016). Parallel Costimulation of Effector and Regulatory T Cells by OX40, GITR, TNFRSF25, CD27, and CD137: Implications for Cancer Immunotherapy. In: Rennert, P. (eds) Novel Immunotherapeutic Approaches to the Treatment of Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-29827-6_3

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