Mechanism of resistance to immune checkpoint inhibitors

Manu R. Pandey , Marc S. Ernstoff

Cancer Drug Resistance ›› 2019, Vol. 2 ›› Issue (2) : 178 -188.

PDF
Cancer Drug Resistance ›› 2019, Vol. 2 ›› Issue (2) :178 -188. DOI: 10.20517/cdr.2018.015
Review
Review

Mechanism of resistance to immune checkpoint inhibitors

Author information +
History +
PDF

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer over the last decade. Instead of targeting the cancer cell directly these agents work by augmenting the immune response towards tumor. Although they are associated with improved responses compared to traditional treatments in several malignancies, a majority of the patients don't respond to ICIs even when used in the frontline setting. In patients who do respond, a significant number eventually develop resistance. We will review ICI mechanisms of action and resistance. We will also discuss new therapeutic options and combinations with other agents that are currently being evaluated to overcome resistance to ICI.

Keywords

Immune checkpoint inhibitors / checkpoint inhibitors / resistance / mechanism

Cite this article

Download citation ▾
Manu R. Pandey, Marc S. Ernstoff. Mechanism of resistance to immune checkpoint inhibitors. Cancer Drug Resistance, 2019, 2(2): 178-188 DOI:10.20517/cdr.2018.015

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Hodi FS,McDermott DF,Sosman JA.Improved survival with ipilimumab in patients with metastatic melanoma..N Engl J Med2010;363:711-23 PMCID:PMC3549297

[2]

Robert C,Bondarenko I,Weber J.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma..N Engl J Med2011;364:2517-26

[3]

Robert C,Long GV,Grob JJ.Pembrolizumab versus Ipilimumab in Advanced Melanoma..N Engl J Med2015;372:2521-32

[4]

Robert C,Brady B,Maio M.Nivolumab in previously untreated melanoma without BRAF mutation..N Engl J Med2015;372:320-30

[5]

Borghaei H,Horn L,Steins M.Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer..N Engl J Med2015;373:1627-39 PMCID:PMC5705936

[6]

Powles T,van der Heijden MS,Vogelzang NJ.Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial..Lancet2018;391:748-57

[7]

Gettinger SN,Gandhi L,Antonia SJ.Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer..J Clin Oncol2015;33:2004-12 PMCID:PMC4672027

[8]

Schachter J,Long GV,Grob JJ.Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)..Lancet2017;390:1853-62

[9]

Larkin J,Gonzalez R,Cowey CL.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma..N Engl J Med2015;373:23-34 PMCID:PMC5698905

[10]

Miller J,Cook K,Sanchez-Lockhart M.Two pathways of costimulation through CD28..Immunol Res2009;45:159-72

[11]

Walunas TL,Bakker CY,Freeman GJ.CTLA-4 can function as a negative regulator of T cell activation..Immunity1994;1:405-13

[12]

Parry RV,Frauwirth KA,Braunstein I.CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms..Mol Cell Biol2005;25:9543-53 PMCID:PMC1265804

[13]

Qureshi OS,Nakamura K,Manzotti C.Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4..Science2011;332:600-3 PMCID:PMC3198051

[14]

Wing K,Prieto-Martin P,Miyara M.CTLA-4 control over Foxp3+ regulatory T cell function..Science2008;322:271-5

[15]

Ahmadzadeh M,Heemskerk B,Dudley ME.Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired..Blood2009;114:1537-44 PMCID:PMC2927090

[16]

Dong H,Salomao DR,Hirano F.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion..Nat Med2002;8:793-800

[17]

Yokosuka T,Kobayashi-Imanishi W,Azuma M.Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2..J Exp Med2012;209:1201-17 PMCID:PMC3371732

[18]

Francisco LM,Brown KE,Freeman GJ.PD-L1 regulates the development, maintenance, and function of induced regulatory T cells..J Exp Med2009;206:3015-29 PMCID:PMC2806460

[19]

Schumacher TN.Neoantigens in cancer immunotherapy..Science2015;348:69-74

[20]

Lawrence MS,Mermel CH,Garraway LA.Discovery and saturation analysis of cancer genes across 21 tumour types..Nature2014;505:495-501 PMCID:PMC4048962

[21]

Alexandrov LB,Wedge DC,Behjati S.Signatures of mutational processes in human cancer..Nature2013;500:415-21 PMCID:PMC3776390

[22]

Rizvi NA,Snyder A,Makarov V.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer..Science2015;348:124-8 PMCID:PMC4993154

[23]

Snyder A,Merghoub T,Zaretsky JM.Genetic basis for clinical response to CTLA-4 blockade in melanoma..N Engl J Med2014;371:2189-99 PMCID:PMC4315319

[24]

Royal RE,Turner K,Hughes M.Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma..J Immunother2010;33:828-33

[25]

Deng L,Burnette B,Darga T.Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice..J Clin Invest2014;124:687-95 PMCID:PMC3904601

[26]

Menard C,Apetoh L,Ghiringhelli F.Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity..Cancer Immunol Immunother2008;57:1579-87

[27]

Ribas A,Puzanov I,Andtbacka RHI.Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy..Cell2017;170:1109-19 e10

[28]

Gerlinger M,Horswell S,Larkin J.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing..N Engl J Med2012;366:883-92 PMCID:PMC4878653

[29]

McGranahan N,Rosenthal R,Lyngaa R.Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade..Science2016;351:1463-9 PMCID:PMC4984254

[30]

Day RS.Treatment sequencing, asymmetry, and uncertainty: protocol strategies for combination chemotherapy..Cancer Res1986;46:3876-85

[31]

Hugo W,Sun L,Moreno BH.Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma..Cell2017;168:542

[32]

Jerby-Arnon L,Cuoco MS,Su MJ.A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade..Cell2018;175:984-97.e24 PMCID:PMC6410377

[33]

Schaer DA,Dempsey JA,Forest A.The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade..Cell Rep2018;22:2978-94

[34]

del Campo AB,Carretero J,Mendez R.Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma..Int J Cancer2014;134:102-13

[35]

Anagnostou V,Forde PM,Bhattacharya R.Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer..Cancer Discov2017;7:264-76 PMCID:PMC5733805

[36]

Mulligan JK,Gillespie MB,Young MR.Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions..Hum Immunol2009;70:375-82 PMCID:PMC2746465

[37]

Oyama T,Ishida T,Kerr L.Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells..J Immunol1998;160:1224-32

[38]

Shrimali RK,Theoret MR,Restifo NP.Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer..Cancer Res2010;70:6171-80 PMCID:PMC2912959

[39]

Hodi FS,Lezcano C,Zhou J.Bevacizumab plus ipilimumab in patients with metastatic melanoma..Cancer Immunol Res2014;2:632-42 PMCID:PMC4306338

[40]

Peng W,Liu C,Creasy C.Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy..Cancer Discov2016;6:202-16 PMCID:PMC4744499

[41]

George S,Demetri GD,Rodig SJ.Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma..Immunity2017;46:197-204 PMCID:PMC5408320

[42]

Holtzhausen A,Evans KS,Orabona C.Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy..Cancer Immunol Res2015;3:1082-95 PMCID:PMC4927300

[43]

Spranger S,Gajewski TF.Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity..Nature2015;523:231-5

[44]

Skoulidis F,Greenawalt DM,Awad MM.STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma..Cancer Discov2018;8:822-35 PMCID:PMC6030433

[45]

Zaretsky JM,Shin DS,Hugo W.Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma..N Engl J Med2016;375:819-29 PMCID:PMC5007206

[46]

Gao J,Zhao H,Xiong L.Loss of IFN-gamma Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy..Cell2016;167:397-404 e9 PMCID:PMC5088716

[47]

Sigalotti L,Coral S.Epigenetic drugs as immunomodulators for combination therapies in solid tumors..Pharmacol Ther2014;142:339-50

[48]

Coral S,Altomonte M,Colizzi F.5-aza-2’-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications..Clin Cancer Res2002;8:2690-5

[49]

Fonsatti E,Sigalotti L,Pezzani L.Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2’-deoxycytidine in cutaneous melanoma: immunotherapeutic implications..Clin Cancer Res2007;13:3333-8

[50]

Woods DM,Cheng F,Perez-Villarroel P.The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity..Melanoma Res2013;23:341-8 PMCID:PMC4012016

[51]

Peng D,Nagarsheth N,Wei S.Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy..Nature2015;527:249-53 PMCID:PMC4779053

[52]

Aspeslagh S,Soria JC.Epigenetic modifiers as new immunomodulatory therapies in solid tumours..Ann Oncol2018;29:812-24

[53]

Daver N,Basu S,Alfayez M.Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study..Cancer Discov2018; PMCID:PMC6397669

[54]

Zhu C,Kuchroo VK.TIM-3 and its regulatory role in immune responses..Curr Top Microbiol Immunol2011;350:1-15

[55]

Wherry EJ,Kaech SM,Sarkar S.Molecular signature of CD8+ T cell exhaustion during chronic viral infection..Immunity2007;27:670-84

[56]

Thommen DS,Muller P,Roller A.Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors..Cancer Immunol Res2015;3:1344-55

[57]

Koyama S,Li YY,Buczkowski KA.Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints..Nat Commun2016;7:10501 PMCID:PMC4757784

[58]

Kim JE,Mangraviti A,Theodros D.Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas..Clinical Cancer Research2017;23:124-36 PMCID:PMC5735836

[59]

Chauvin JM,Fourcade J,Wang H.TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients..J Clin Invest2015;125:2046-58 PMCID:PMC4463210

[60]

Kuklinski LF,Li Z,Cheng C.VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival..Cancer Immunol Immunother2018;67:1113-21

[61]

Blackburn SD,Freeman GJ.Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade..Proc Natl Acad Sci U S A2008;105:15016-21 PMCID:PMC2567485

[62]

Blackburn SD,Haining WN,Workman CJ.Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection..Nat Immunol2009;10:29-37 PMCID:PMC2605166

[63]

Wherry EJ,Murali-Krishna K,Ahmed R.Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment..J Virol2003;77:4911-27 PMCID:PMC152117

[64]

Daud AI,Pauli ML,Sandoval PM.Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma..J Clin Invest2016;126:3447-52 PMCID:PMC5004965

[65]

Schietinger A,Krisnawan VE,Delrow JJ.Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis..Immunity2016;45:389-401 PMCID:PMC5119632

[66]

Philip M,Sun L,Camara S.Chromatin states define tumour-specific T cell dysfunction and reprogramming..Nature2017;545:452-6 PMCID:PMC5693219

[67]

Gabrilovich DI,Bronte V.Coordinated regulation of myeloid cells by tumours..Nat Rev Immunol2012;12:253-68 PMCID:PMC3587148

[68]

Sade-Feldman M,Klieger Y,Olga M.Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab..Clin Cancer Res2016;22:5661-72

[69]

Gebhardt C,Jiang H,Reith M.Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab..Clin Cancer Res2015;21:5453-9

[70]

Weber J,Kudchadkar R,Cheng P.Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab..Cancer Immunol Res2016;4:345-53 PMCID:PMC4818672

[71]

Highfill SL,Giles AJ,Zhang H.Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy..Sci Transl Med2014;6:237ra67

[72]

De Henau O,Winkler D,Liu C.Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells..Nature2016;539:443-7 PMCID:PMC5634331

[73]

Christmas BJ,Hopkins AC,Ma HS.Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs..Cancer Immunol Res2018;6:1561-77 PMCID:PMC6279584

[74]

Ornstein MC,Rayman P,Haywood S.Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy..Urol Oncol2018;36:405-12

[75]

Steidl C,Shah SP,Han G.Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma..N Engl J Med2010;362:875-85 PMCID:PMC2897174

[76]

Kurahara H,Mataki Y,Noma H.Significance of M2-polarized tumor-associated macrophage in pancreatic cancer..J Surg Res2011;167:e211-9

[77]

DeNardo DG,Rexhepaj E,Shiao SL.Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy..Cancer Discov2011;1:54-67 PMCID:PMC3203524

[78]

Strachan DC,Oei Y,Coussens LM.CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8(+) T cells..Oncoimmunology2013;2:e26968 PMCID:PMC3902121

[79]

Ries CH,Hoves S,Wartha K.Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy..Cancer Cell2014;25:846-59

[80]

Zhu Y,Meyer MA,West BL.CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models..Cancer Res2014;74:5057-69 PMCID:PMC4182950

[81]

van Baren N.Tryptophan-degrading enzymes in tumoral immune resistance..Front Immunol2015;6:34 PMCID:PMC4315104

[82]

Hwu P,Lapointe R,Taylor MW.Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation..J Immunol2000;164:3596-9

[83]

Uyttenhove C,Theate I,Colau D.Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase..Nat Med2003;9:1269-74

[84]

Frumento G,Tonetti M,Benatti U.Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase..J Exp Med2002;196:459-68 PMCID:PMC2196046

[85]

Holmgaard RB,Munn DH,Allison JP.Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4..J Exp Med2013;210:1389-402 PMCID:PMC3698523

[86]

Wainwright DA,Dey M,Kim CK.Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors..Clin Cancer Res2014;20:5290-301 PMCID:PMC4182350

[87]

Long GV,Hamid O,Caglevic C.Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study..J Clin Oncol2018;36:108

[88]

Gibney GT,Gangadhar TC,Olszanski AJ.Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma..J Clin Oncol2014;32:3010

[89]

Jin D,Wang L,Liu A.CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression..Cancer Res2010;70:2245-55 PMCID:PMC2883609

[90]

Allard B,Smyth MJ.Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs..Clin Cancer Res2013;19:5626-35

[91]

Massague J.TGFbeta in Cancer..Cell2008;134:215-30 PMCID:PMC3512574

[92]

Thomas DA.TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance..Cancer Cell2005;8:369-80

[93]

Hanks BA,Evans K,Blobe GC.Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma..J Clin Oncol2014;32:3011

[94]

de Gramont A,Raymond E.Novel TGF-beta inhibitors ready for prime time in onco-immunology..Oncoimmunology2017;6:e1257453 PMCID:PMC5283641

[95]

La Shu S,Allen CL,Minderman H.Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment..Sci Rep2018;8:12905 PMCID:PMC6110845

[96]

Tuccitto A,Beretta V,Miranda C.Immunomodulatory factors control the fate of melanoma tumor initiating cells..Stem Cells2016;34:2449-60

[97]

Hugo W,Sun L,Song C.Non-genomic and immune evolution of melanoma acquiring MAPKi resistance..Cell2015;162:1271-85 PMCID:PMC4821508

[98]

Ackerman A,McDermott DF,Ibrahim N.Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors..Cancer2014;120:1695-701

[99]

Sharma P,Wargo JA.Primary, adaptive, and acquired resistance to cancer immunotherapy..Cell2017;168:707-23 PMCID:PMC5391692

AI Summary AI Mindmap
PDF

368

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/