Abstract
Immune checkpoint blockades (ICBs), as a major breakthrough in cancer immunotherapy, target CTLA-4 and the PD-1/PD-L1 axis and reinvigorate anti-tumor activities by disrupting co-inhibitory T-cell signaling. With unprecedented performance in clinical trials, ICBs have been approved by FDA for the treatment of malignancies such as melanoma, non-small-cell lung cancer, colorectal cancer, and hepatocellular carcinoma. However, while ICBs are revolutionizing therapeutic algorithms for cancers, the frequently observed innate, adaptive or acquired drug resistance remains an inevitable obstacle to a durable antitumor activity, thus leading to non-response or tumor relapse. Researches have shown that resistance could occur at each stage of the tumor’s immune responses. From the current understanding, the molecular mechanisms for the resistance of ICB can be categorized into the following aspects: 1. Tumor-derived mechanism, 2. T cell-based mechanism, and 3. Tumor microenvironment-determined resistance. In order to overcome resistance, potential therapeutic strategies include enhancing antigen procession and presentation, reinforcing the activity and infiltration of T cells, and destroying immunosuppression microenvironment. In future, determining the driving factors behind ICB resistance by tools of precision medicine may maximize clinical benefits from ICBs. Moreover, efforts in individualized dosing, intermittent administration and/or combinatory regimens have opened new directions for overcoming ICB resistance.
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References
Abiko K et al (2015) IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 112(9):1501
Administration UFaD (2016) Keytruda. Highlights of prescribing information
Administration UFaD (2017) Highlights of prescribing information. Tecentriq (atezolizumab) injection, for intravenous use
Administration UFaD (2017) Avelumab (Bavencio). Highlights of prescribing information
Administration UFaD (2018) Imfinzi (durvalumab). Prescribing information. FDA
Akbay EA et al (2013) Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 3(12):1355–1363
Ali K et al (2014) Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510(7505):407–411
Anderson AC et al (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44(5):989–1004
Ansell SM et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319
Antonia SJ et al (2017) Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 377(20):1919–1929
Arlauckas SP et al (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9(389)
Atkins MB et al (2014) Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. J Clin Oncol 32
Atri C, Guerfali F, Laouini D (2018) Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci 19(6):1801
Atsaves V et al (2017) PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. Leukemia 31(7):1633–1637
Bai J et al (2017) Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget 8(66):110693
Beer TM et al (2017) Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 35(1):40–47
Bellmunt J et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376(11):1015–1026
Berger R et al (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 14(10):3044–3051
Bettelli E et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector T H 17 and regulatory T cells. Nature 441(7090):235
Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11(10):889–896
Blank C et al (2004) PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64(3):1140–1145
Bommareddy PK, Shettigar M, Kaufman HL (2018) Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol 18(8):498–513
Boni A et al (2010) Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 70(13):5213–5219
Borghaei H et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 373(17):1627–1639
Bourgeois-Daigneault MC et al (2018) Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med 10(422)
Bradley SD et al (2015) BRAFV600E Co-opts a Conserved MHC Class I internalization pathway to diminish antigen presentation and CD8 + T-cell recognition of melanoma. Cancer Immunol Res 3(6):602–609
Brahmer JR et al (2012) Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465
Brahmer J et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373(2):123–135
Brunet J-F et al (1987) A new member of the immunoglobulin superfamily—CTLA-4. Nature 328(6127):267
Callahan MK et al (2014) Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol Res 2(1):70–79
Casey SC et al (2016) MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352(6282):227–231
Cella D et al (2019) Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol 20(2):297–310
Chakravarthy A et al (2018) TGF-beta-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 9(1):4692
Chang DK et al (2012) Humanization of an anti-CCR4 antibody that kills cutaneous T-cell lymphoma cells and abrogates suppression by T-regulatory cells. Mol Cancer Ther 11(11):2451–2461
Chanmee T et al (2014) Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 6(3):1670–1690
Chaudhary B, Elkord E (2016) Regulatory T Cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel) 4(3)
Chauvin JM et al (2015) TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest 125(5):2046–2058
Chen DS, Irving BA, Hodi FS (2012) Molecular pathways: next-generation immunotherapy-inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18(24):6580–6587
Chen S et al (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 R et al (2017) Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35(19):2125–2132
Choi YJ et al (2012) The requirement for cyclin D function in tumor maintenance. Cancer Cell 22(4):438–451
Chow LQ et al (2016) Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 34(32):3838–3845
Chowell D et al (2018) Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359(6375):582–587
Cooper ZA et al (2014) Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res 2(7):643–654
Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421
Davies LC, Taylor PR (2015) Tissue-resident macrophages: then and now. Immunology 144(4):541–548
Davis RJ et al (2017) Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kdelta/gamma. Cancer Res 77(10):2607–2619
Deng L et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124(2):687–695
Disis ML et al (2016) Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: safety and clinical activity. J Clin Oncol 34:5533
Dong H et al (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5(12):1365
Dorand RD et al (2016) Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science 353(6297):399–403
Dovedi SJ et al (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74(19):5458–5468
Dovedi SJ et al (2017) Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res 23(18):5514–5526
Dunn GP et al (2005) A critical function for type I interferons in cancer immunoediting. Nat Immunol 6(7):722–729
El-Khoueiry AB et al (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389(10088):2492–2502
Elpek KG et al (2007) CD4 + CD25 + T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J Immunol 178(11):6840–6848
Fang W et al (2018) Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol 19(10):1338–1350
Fares CM et al (2019) Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book 39:147–164
Feig C et al (2013a) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci 110(50):20212–20217
Feig C et al (2013b) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 110(50):20212–20217
Feig C et al (2013c) Targeting CXCL12 from FAP-expressing carcinomaassociated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110(50):20212–20217
Ferris RL et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867
Festino L et al (2016) Cancer treatment with anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs 76(9):925–945
Flaherty KT (2012) Targeting metastatic melanoma. Annu Rev Med 63(9):171
Freeman GJ et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034
Fried I et al (2018) Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma. J Neurooncol 136(1):189–195
Fritz JM et al (2014) Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. Front Immunol 5:587
Fuchs CS et al (2018) Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 4(5):e180013–e180013
Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253
Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022
Gandhi L et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092
Gao J et al (2017) VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23(5):551–555
George S et al (2017) Loss of PTEN is associated with resistance to anti-pd-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46(2):197–204
Gil M et al (2014) CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J Immunol 193(10):5327–5337
Gong X et al (2017) Combined radiotherapy and Anti-PD-L1 antibody synergistically enhances antitumor effect in non-small cell lung cancer. J Thorac Oncol 12(7):1085–1097
Gong B et al (2019) Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer. J Exp Med 216(4):982–1000
Govindan R et al (2017) Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 35(30):3449–3457
Gray-Owen SD, Blumberg RS (2006) CEACAM1: contact-dependent control of immunity. Nat Rev Immunol 6(6):433–446
Grinberg-Bleyer Y et al (2017) NF-kappaB c-Rel is crucial for the regulatory T Cell immune checkpoint in cancer. Cell 170(6):1096–1108.e13
Gubin MM et al (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528):577–581
Guerriero JL et al (2017) Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543(7645):428–432
Gulley JL et al (2015) Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: a phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J Clin Oncol 33:8034
Hamanishi J et al (2015) Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. J Clin Oncol 33:5570
Hamid O et al (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204
Hamid O et al (2013a) Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med 369(2):134–144
Hamid O et al (2013b) Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol 31:9010
Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21(3):309–322
Hanks B.A et al (2014) Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/-transgenic model of melanoma. In: Asco annual meeting proceedings
Hardy B et al (1997) A lymphocyte-activating monoclonal antibody induces regression of human tumors in severe combined immunodeficient mice. Proc Natl Acad Sci USA 94(11):5756–5760
Hargadon KM, Johnson CE, Williams CJ (2018) Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol 62:29–39
Haymaker CL et al (2017) Metastatic melanoma patient had a complete response with clonal expansion after whole brain radiation and PD-1 blockade. Cancer Immunol Res 5(2):100–105
Hellmann MD et al (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18(1):31–41
Hellmann MD et al (2019) Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell 35(2):329
Herbst RS et al (2013) A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol 31:3000
Highfill S.L et al (2014) Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 6(237):237ra67–237ra67
Highfill S.L et al (2014) Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 6(237):237ra67
Hodges TR et al (2017) Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol 19(8):1047–1057
Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723
Holmgaard RB et al (2013) Indoleamine 2, 3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 210(7):1389–1402
Hu W et al (2016) Tumor-associated macrophages in cancers. Clin Transl Oncol 18(3):251–258
Huang AC et al (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545(7652):60–65
Huang J et al (2018) Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res 24(6):1296–1304
Huang J et al (2019) Promising efficacy of SHR-1210, a novel anti–programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China. Cancer 125(5):742–749
Hughes PE, Caenepeel S, Wu LC (2016) Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol 37(7):462–476
Hugo W et al (2015) Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162(6):1271–1285
Hugo W et al (2016) Genomic and transcriptomic features of response to Anti-PD-1 therapy in metastatic melanoma. Cell 165(1):35–44
Ishida Y et al (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11(11):3887–3895
Ishizuka JJ et al (2019) Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565(7737):43–48
Jbag H (2017) Converting cold into hot tumors by combining immunotherapies. Cell 170(6):1055–1056
Jenkins RW, Barbie DA, Flaherty KT (2018) Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 118(1):9–16
Jiao S et al (2017) PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 23(14):3711–3720
John LB et al (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19(20):5636–5646
Kalbasi A, Ribas A (2019) Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol
Kaneda MM et al (2016) PI3Kgamma is a molecular switch that controls immune suppression. Nature 539(7629):437–442
Kaplan MH, Wurster AL, Grusby MJ (1998) A signal transducer and activator of transcription (Stat)4-independent pathway for the development of T helper type 1 cells. J Exp Med 188(6):1191–1196
Kataoka K et al (2016) Aberrant PD-L1 expression through 3’-UTR disruption in multiple cancers. Nature 534(7607):402–406
Kaufman HL et al (2016) Avelumab in patients with chemotherapy-refractory metastatic merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385
Kim K et al (2014) Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A 111(32):11774–11779
Koyama S et al (2016a) STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress t-cell activity in the lung tumor microenvironment. Cancer Res 76(5):999–1008
Koyama S et al (2016b) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 7:10501
Kryczek I et al (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203(4):871–881
Kuang DM et al (2009) Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 206(6):1327–1337
Lan Y et al (2018) Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-beta. Sci Transl Med 10(424)
Larkin J et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34
Lastwika KJ et al (2016) Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res 76(2):227–238
Le DT et al (2013) Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 36(7):382–389
Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736
Lebrun JJ (2012) The dual role of TGFbeta in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol 2012:381428
Lin RL, Zhao LJ (2015) Mechanistic basis and clinical relevance of the role of transforming growth factor-beta in cancer. Cancer Biol Med 12(4):385–393
Linehan DC, Goedegebuure PS (2005) CD25 + CD4 + regulatory T-cells in cancer. Immunol Res 32(1–3):155–168
Lipson EJ, Drake CG (2011) Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res 17(22):6958–6962
Liu C et al (2013) BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 19(2):393–403
Liu J et al (2015) Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A 112(21):6682–6687
Liu X et al (2016) A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res 76(6):1578–1590
Locarnini SA, Yuen L (2010) Molecular genesis of drug-resistant and vaccine-escape HBV mutants. Antivir Ther 15(3 Pt B):451–461
Luo Y et al (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116(8):2132–2141
Mace TA et al (2018) IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67(2):320–332
Mantovani A et al (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14(7):399–416
Mariathasan S et al (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554(7693):544
Maruyama D et al (2017) Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Cancer Sci 108(5):1007–1012
Marzec M et al (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci USA 105(52):20852–20857
Massague J (2008) TGFbeta in Cancer. Cell 134(2):215–230
Mayes PA, Hance KW, Hoos A (2018) The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov 17(7):509–527
Mcconnell JL, Wadzinski BE (2009) Targeting protein serine/threonine phosphatases for drug development. Mol Pharmacol 75(6):1249–1261
McDermott DF et al (2016) Atezolizumab, an anti–programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 34(8):833–842
McKee SJ et al (2017) Therapeutic efficacy of 4-1BB costimulation is abrogated by PD-1 blockade in a model of spontaneous B-cell lymphoma. Cancer Immunol Res 5(3):191–197
Meder L et al (2018) Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res 78(15):4270–4281
Messenheimer DJ et al (2017) Timing of PD-1 blockade is critical to effective combination immunotherapy with anti-OX40. Clin Cancer Res 23(20):6165–6177
Meyer C et al (2014) Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 63(3):247–257
Mitchell TC et al (2018) Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase i results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol:Jco2018789602
Motzer RJ et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813
Motzer RJ et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14):1277–1290
Muller J et al (2014) Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun 5:5712
Ngiow SF et al (2016) Agonistic CD40 mAb-Driven IL12 reverses resistance to Anti-PD1 in a T-cell-Rich tumor. Cancer Res 76(21):6266–6277
Nishio M et al (2017) Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer. ESMO Open 1(4):e000108
Nowak AK, Robinson BW, Lake RA (2003) Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 63(15):4490–4496
Ohtsukasa S et al (2003) Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs. J Cancer Res Clin Oncol 129(12):719–726
Oida T et al (2003) CD4 + CD25- T cells that express latency-associated peptide on the surface suppress CD4 + CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism. J Immunol 170(5):2516–2522
Orillion A et al (2017) Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res 23(17):5187–5201
Ormandy LA et al (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65(6):2457–2464
Ott PA et al (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547(7662):217–221
Overman MJ et al (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18(9):1182–1191
Overman MJ et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36(8):773–779
Park Y-J, Kuen D-S, Chung Y (2018) Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance. Exp Mol Med 50(8):1–13
Parsa AT et al (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88
Patel MR et al (2018) Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19(1):51–64
Pauken KE et al (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354(6316):1160–1165
Peng J et al (2015) Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear Factor-kappaB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res 75(23):5034–5045
Peng W et al (2016) Loss of PTEN promotes resistance to t cell-mediated immunotherapy. Cancer Discov 6(2):202–216
Platten M, Wick W, Van den Eynde BJ (2012) Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res 72(21):5435–5440
Polivka J Jr, Janku F (2014) Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 142(2):164–175
Prasad V, Kaestner V, Mailankody S (2018) Cancer drugs approved based on biomarkers and not tumor type—FDA approval of pembrolizumab for mismatch repair-deficient solid cancers. JAMA Oncol 4(2):157–158
Prendergast GC et al (2017) Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res 77(24):6795–6811
Prestwich RJ et al (2008) Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clin Cancer Res 14(22):7358–7366
Puzanov I et al (2016) Talimogene Laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol 34(22):2619–2626
Quezada SA et al (2006) CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116(7):1935–1945
Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12(4):269–281
Ribas A (2015a) Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov 5(9):915–919
Ribas A et al (2015) Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol 33(15_suppl):3003–3003
Ribas A et al (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 31(5):616
Ribas A et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918
Ribas A et al (2019) Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat Med 25(6):936–940
Rittmeyer A et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265
Robert C et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526
Robert C et al (2015a) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330
Robert C et al (2015b) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532
Rooney MS et al (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1–2):48–61
Rosenberg JE et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387(10031):1909–1920
Rubinfeld B et al (2006) Identification and immunotherapeutic targeting of antigens induced by chemotherapy. Nat Biotechnol 24(2):205–209
Sadreddini S et al (2019) Immune checkpoint blockade opens a new way to cancer immunotherapy. J Cell Physiol 234(6):8541–8549
Saha D, Martuza RL, Rabkin SD (2017) Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell 32(2):253–267.e5
Sahin U, Tureci O (2018) Personalized vaccines for cancer immunotherapy. Science 359(6382):1355–1360
Sakaguchi S et al (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787
Sakuishi K et al (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207(10):2187–2194
Saleh R, Elkord E (2019) Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett 457:168–179
Salmon H et al (2012) Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 122(3):899–910
Schachter J et al (2017) Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390(10105):1853–1862
Schadendorf D et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894
Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348(6230):69–74
Sharabi A et al (2017) Exceptional response to nivolumab and Stereotactic Body Radiation Therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: management considerations from the center for personalized cancer therapy at UC San Diego Moores cancer center. Oncologist 22(6):631–637
Sharma P et al (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214
Sharma P et al (2017a) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723
Sharma P et al (2017b) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18(3):312–322
Shin DS et al (2017) Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 7(2):188–201
Singh M et al (2017) Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Nat Commun 8(1):1447
Solito S et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118(8):2254–2265
Spranger S, Bao R, Gajewski T (2014a) Melanoma-intrinsic β-catenin signaling prevents T cell infiltration and anti-tumor immunity. J Immunother Cancer 2(S3):O15
Spranger S et al (2014b) Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8 + T cells directly within the tumor microenvironment. J Immunother Cancer 2(1):3
Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523(7559):231–235
Squibb B-M (2015) Opdivo®(nivolumab)[Package insert]. Princeton, NJ, Bristol-Myers Squibb
Squibb E, Sons L (2018) Prescribing information: YERVOY®(ipilimumab) injection for intravenous use 2015
Stagg J et al (2010) Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A 107(4):1547–1552
Steinberg SM et al (2017) Myeloid cells that impair immunotherapy are restored in melanomas with acquired resistance to BRAF inhibitors. Cancer Res 77(7):1599–1610
Suarez ER et al (2016) Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7(23):34341–34355
Sugiyama D et al (2013) Anti-CCR4 mAb selectively depletes effector-type FoxP3 + CD4 + regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A 110(44):17945–17950
Sun Z et al (2015) IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8 + T cells. Cancer Res 75(8):1635–1644
Sundstedt A et al (2003) Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol 170(3):1240–1248
Takahashi H et al (1993) Differential regulation of carcinoembryonic antigen and biliary glycoprotein by gamma-interferon. Cancer Res 53(7):1612–1619
Tang B et al (2019) Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol 12(1):7
Taylor NA et al (2017) Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer. J Clin Invest 127(9):3472–3483
Tham M et al (2015) Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma. Oncotarget 6(26):22857–22868
Togashi Y, Shitara K, Nishikawa H (2019) Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol 16(6):356–371
Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461
Tsukamoto H et al (2018) Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res 78(17):5011–5022
Tumeh PC et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571
Twumasi-Boateng K et al (2018) Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer 18(7):419–432
Twyman-Saint Victor C et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547):373–377
Tykodi SS et al (2012) PD-1/PD-L1 pathway as a target for cancer immunotherapy: safety and clinical activity of BMS-936559, an anti-PD-L1 antibody, in patients with solid tumors. J Clin Oncol 30:2510
van Rooij N et al (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31(32):e439–e442
Vargas FA et al (2017) Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity 46(4):577–586
Viehl CT et al (2006) Depletion of CD4 + CD25 + regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol 13(9):1252–1258
Vo DD et al (2009) Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res 69(22):8693–8699
Walunas TL et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1(5):405–413
Wang B et al (2018) Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8(+) T cell dysfunction and maintain memory phenotype. Sci Immunol 3(29)
Wang LX et al (2013) Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS ONE 8(5):e62924
Weber JS et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384
Wesolowski R, Markowitz J, Carson WE 3rd (2013) Myeloid derived suppressor cells—a new therapeutic target in the treatment of cancer. J Immunother Cancer 1:10
Wierz M et al (2018) Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood 131(14):1617–1621
Woo EY et al (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168(9):4272–4276
Woo SR et al (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72(4):917–927
Wu X et al (2014) Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. J Invest Dermatol 134(11):2814–2822
Xue J et al (2019) Intrinsic beta-catenin signaling suppresses CD8(+) T-cell infiltration in colorectal cancer. Biomed Pharmacother 115:108921
Yang L et al (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421
Yang L et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13(1):23–35
Yang X et al (2016) FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3–CCL2 signaling. Cancer Res 76(14):4124–4135
Younes A et al (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17(9):1283–1294
Zamarin D et al (2014) Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 6(226):226ra32
Zboralski D et al (2017) Increasing tumor-infiltrating T Cells through inhibition of CXCL12 with NOX-A12 synergizes with PD-1 blockade. Cancer Immunol Res 5(11):950–956
Zhang H et al (2004) Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3’,5’-monophosphate and phosphatases. J Immunol 173(2):932–944
Zhou J et al (2018) Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut 67(5):931–944
Zhu Y et al (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
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Shi, H., Lan, J., Yang, J. (2020). Mechanisms of Resistance to Checkpoint Blockade Therapy. In: Xu, J. (eds) Regulation of Cancer Immune Checkpoints. Advances in Experimental Medicine and Biology, vol 1248. Springer, Singapore. https://doi.org/10.1007/978-981-15-3266-5_5
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