Biomarkers of resistance to immune checkpoint inhibitors in non-small-cell lung cancer: myth or reality?

Abstract

Immune checkpoint inhibitors represent a major therapeutic advance in non-small-cell lung cancer with several approved anti-programmed death-1 and anti-programmed death-L1 immunotherapies. A majority of patients however, will not respond to immune checkpoint inhibitors and display primary resistance while a subset of initially responsive patients will present secondary resistance. Thus, there is a crucial need for biomarkers to enable better prediction and diagnosis, and to overcome such resistance. Along with improvement in the understanding of immune escape, new biomarkers are being developed, including large scale proteomic, genomic and transcriptomic approaches in tumor and blood samples. We review the novel biomarkers that have been investigated in non-small-cell lung cancer and discuss how they can rationalize therapeutic strategies.

Keywords

Non-small-cell lung cancer / immune checkpoint inhibitors / resistance / predictive biomarkers / diagnostic biomarkers / programmed death ligand-1 / tumor mutational burden / circulating tumor DNA

References

[1] Garon EB,Hui R,Balmanoukian AS.Pembrolizumab for the treatment of non-small-cell lung cancer..N Engl J Med2015;372:2018-28

[2] Brahmer J,Baas P,Eberhardt WE.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer..N Engl J Med2015;373:123-35 PMCID:PMC4681400

[3] 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

[4] Herbst RS,Kim DW,Pérez-Gracia JL.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial..Lancet2016;387:1540-50

[5] Rittmeyer A,Waterkamp D,Ciardiello F.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial..Lancet2017;389:255-65 PMCID:PMC6886121

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

[7] Fares CM,Drake CG,Hu-Lieskovan S.Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients?.Am Soc Clin Oncol Educ Book2019;39:147-64

[8] Reck M,Robinson AG,Csőszi T.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer..N Engl J Med2016;375:1823-33

[9] Carbognin L,Milella M,Brunelli M.Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers..PLoS One2015;10:e0130142 PMCID:PMC4472786

[10] Kulangara K,Corigliano E,Waldroup S.Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer..Arch Pathol Lab Med2019;143:330-7

[11] Takamori S,Toyokawa G,Shimokawa M.PD-L2 expression as a potential predictive biomarker for the response to Anti-PD-1 drugs in patients with non-small cell lung cancer..Anticancer Res2018;38:5897-901

[12] Yearley JH,Yu N,Murphy E.PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer..Clin Cancer Res2017;23:3158-67

[13] Lantuejoul S,Cooper WA,Hirsch FR.PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee..J Thorac Oncol2020;15:499-519

[14] Kerr KM.The PD-L1 immunohistochemistry biomarker: two steps forward, one step back?.J Thorac Oncol2018;13:291-4

[15] Garon EB,Rizvi NA,Leighl NB.Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study..J Clin Oncol2019;37:2518-27 PMCID:PMC6768611

[16] Saleh R.Acquired resistance to cancer immunotherapy: role of tumor-mediated immunosuppression..Semin Cancer Biol2019;JulyS1044-579X(19)30171-3

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

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

[19] Yarchoan M,Jaffee EM.Tumor mutational burden and response rate to PD-1 inhibition..N Engl J Med2017;377:2500-1 PMCID:PMC6549688

[20] Rizvi H,La K,Jonsson P.Molecular determinants of response to anti–programmed cell death (PD)-1 and anti–programmed death-ligand 1 (PD-L1) blockade in patients with non–small-cell lung cancer profiled with targeted next-generation sequencing..J Clin Oncol2018;36:633-41 PMCID:PMC6075848

[21] Frampton GM,Otto GA,Downing SR.Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing..Nat Biotechnol2013;31:1023-31 PMCID:PMC5710001

[22] Gandara DR,Kowanetz M,Zou W.Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab..Nat Med2018;24:1441-8

[23] Helman E,Vowles JV,Nance T.Abstract 5603: Analytical validation of a comprehensive 500-gene ctDNA panel designed for immuno-oncology and DNA damage research..Cancer Res2018;78:5603

[24] ESMO immuno-oncology 2018: MYSTIC: first-line durvalumab with or without tremelimumab in metastatic NSCLC - The ASCO Post. Available from: https://www.ascopost.com/News/59583 [Last accessed on 26 Apr 2020]

[25] Vokes NI,Ricciuti B,Rizvi H.Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non-small-cell lung cancer..JCO Precis Oncol2019;3: PMCID:PMC6907021

[26] Meléndez B,Rorive S,Salmon I.Methods of measurement for tumor mutational burden in tumor tissue..Transl Lung Cancer Res2018;7:661 PMCID:PMC6249625

[27] Hellmann MD,Pluzanski A,Otterson GA.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden..N Engl J Med2018;378:2093-104 PMCID:PMC7193684

[28] Bristol-Myers Squibb Reports Fourth Quarter and Full Year Financial Results | BMS Newsroom. Available from: https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-reports-fourth-quarter-and-full-year-fi-0 [Last accessed on 26 Apr 2020]

[29] Park J.Identification of neoantigens derived from alternative splicing and RNA modification..Genomics Inform2019;17:e23 PMCID:PMC6808645

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

[31] Riaz N,Makarov V,Urba WJ.Tumor and microenvironment evolution during immunotherapy with nivolumab..Cell2017;171:934-49.e16 PMCID:PMC5685550

[32] Anagnostou V,White JR,Hruban C.Dynamics of tumor and immune responses during immune checkpoint blockade in non–small cell lung cancer..Cancer Res2019;79:1214-25 PMCID:PMC6432636

[33] Lee CK,Lord S,Gebski V.Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis..J Thorac Oncol2017;12:403-7

[34] Mazieres J,Lusque A,Cortot AB.Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry..Ann Oncol2019;30:1321-8

[35] 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

[36] Friedrich M,Lazaridou MF,Massa C.Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy..Cancer Immunol Immunother2019;68:1689-700

[37] McGranahan N,Hiley CT,Watkins TBK.Allele-specific HLA loss and immune escape in lung cancer evolution..Cell2017;171:1259-71.e11 PMCID:PMC5720478

[38] Shin DS,Escuin-Ordinas H,Hu-Lieskovan S.Primary resistance to PD-1 blockade mediated by JAK1/2 mutations..Cancer Discov2017;7:188-201 PMCID:PMC5296316

[39] Benci JL,Qiu Y,Dada H.Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade..Cell2016;167:1540-54.e12 PMCID:PMC5385895

[40] 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

[41] Higgs BW,Streicher K,Pilataxi F.Interferon gamma messenger RNA signature in tumor biopsies predicts outcomes in patients with non-small cell lung carcinoma or urothelial cancer treated with durvalumab..Clin Cancer Res2018;24:3857-66

[42] Damotte D,Arrondeau J,Mansuet-Lupo A.The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort..J Transl Med2019;17:357 PMCID:PMC6829827

[43] Fehrenbacher L,Ballinger M,Vansteenkiste J.Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial..Lancet2016;387:1837-46

[44] Herbst RS,Kowanetz M,Hamid O.Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients..Nature2014;515:563-7 PMCID:PMC4836193

[45] Hugo W,Sun L,Moreno BH.Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma..Cell2016;165:35-44 PMCID:PMC4808437

[46] Ascierto ML,Berger AE,Anders RA.The intratumoral balance between metabolic and immunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma..Cancer Immunol Res2016;4:726-33 PMCID:PMC5584610

[47] Toulmonde M,Adam J,Blay JY.Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial..JAMA Oncol2018;4:93-7 PMCID:PMC5833654

[48] 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

[49] Volaric A,Hall R,Stelow EB.Indoleamine-2,3-dioxygenase in non-small cell lung cancer: a targetable mechanism of immune resistance frequently coexpressed with PD-L1..Am J Surg Pathol2018;42:1216-23

[50] Botticelli A,Lionetto L,Salati M.Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?.J Transl Med2018;16:219 PMCID:PMC6080500

[51] Nagarsheth N,Zou W.Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy..Nat Rev Immunol2017;17:559-72 PMCID:PMC5731833

[52] Harlin H,Peterson AC,Tretiakova M.Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment..Cancer Res2009;69:3077-85 PMCID:PMC3886718

[53] Badoual C,Merillon N,Ravel P.PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer..Cancer Res2013;73:128-38

[54] Tumeh PC,Yearley JH,Taylor EJ.PD-1 blockade induces responses by inhibiting adaptive immune resistance..Nature2014;515:568-71 PMCID:PMC4246418

[55] Uryvaev A,Hershkovits D,Bar-Sela G.The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma..Med Oncol Northwood Lond Engl2018;35:25

[56] Bonaventura P,Alcazer V,Valsesia-Wittmann S.Cold tumors: a therapeutic challenge for immunotherapy..Front Immunol2019;10: PMCID:PMC6376112

[57] Gunderson AJ,McCarty K,Phillips M.TGFβ suppresses CD8⁺ T cell expression of CXCR3 and tumor trafficking..Nat Commun2020;11:1749 PMCID:PMC7145847

[58] Clarke J,Madrigal A,Gujar R.Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer..J Exp Med2019;216:2128-49 PMCID:PMC6719422

[59] Funt S,Yusko E,Benzeno S.Correlation of peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in patients with metastatic urothelial cancer (mUC) treated with atezolizumab..J Clin Oncol2016;34:3005

[60] Schrama D,Becker JC.T cell receptor repertoire usage in cancer as a surrogate marker for immune responses..Semin Immunopathol2017;39:255-68

[61] Watanabe N,Sedy JR,Fallarino F.BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1..Nat Immunol2003;4:670-9

[62] Koyama S,Li YY,Buczkowski KA.Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints..Nat Commun2016;7:1-9 PMCID:PMC4757784

[63] Thommen DS,Müller 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

[64] Cheng H,Janakiram M,Lin J.Wide expression and significance of alternative immune checkpoint molecules, B7x and HHLA2, in PD-L1-negative human lung cancers..Clin Cancer Res2018;24:1954-64 PMCID:PMC5899616

[65] Datar I,Wang J,Choi J.Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis..Clin Cancer Res2019;25:4663-73

[66] Du W,Cai S,Wu L.Dynamic testing of stimulative and suppressive biomarkers on peripheral blood cells at early stages of immunotherapy predicts response in advanced cancer patients..Discov Med2018;25:277-90

[67] Wherry EJ.Molecular and cellular insights into T cell exhaustion..Nat Rev Immunol2015;15:486-99 PMCID:PMC4889009

[68] Pauken KE,Odorizzi PM,Godec J.Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade..Science2016;354:1160-5 PMCID:PMC5484795

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

[70] Gallimore A,Roychoudhuri R.Regulatory T cells in cancer: where are we now?.Immunology2019;157:187-9 PMCID:PMC6587319

[71] Simpson TR,Montalvo-Ortiz W,Bergerhoff K.Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma..J Exp Med2013;210:1695-710 PMCID:PMC3754863

[72] Kamada T,Tay C,Sasaki A.PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer..Proc Natl Acad Sci2019;116:9999-10008 PMCID:PMC6525547

[73] Meyer C,Costa-Nunes CM,Montandon N.Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab..Cancer Immunol Immunother2014;63:247-57

[74] Routy B,Derosa L,Alou MT.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors..Science2018;359:91-7

[75] Shaikh FY,Sears CL.Impact of the microbiome on checkpoint inhibitor treatment in patients with non-small cell lung cancer and melanoma..EBioMedicine2019;48:642-7 PMCID:PMC6838599

[76] Keren L,Marquez D,Jain S.A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging..Cell2018;174:1373-87.e19 PMCID:PMC6132072

[77] Goltsev Y,Kennedy-Darling J,Hale M.Deep profiling of mouse splenic architecture with CODEX multiplexed imaging..Cell2018;174:968-81.e15 PMCID:PMC6086938

[78] Chen PL,Reuben A,Spencer CN.Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade..Cancer Discov2016;6:827-37 PMCID:PMC5082984

[79] Domagala-Kulawik J,Dziedzic D,Kryczka T.Do two lungs form an integrated immune system? Learning from BALF examination in lung cancer..Ann Oncol2019;30:

[80] Magaki S,Wei B,Yong WH.An introduction to the performance of immunohistochemistry..Methods Mol Biol2019;1897:289-98 PMCID:PMC6749998

[81] Schwarze K,Taylor JC.Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature..Genet Med2018;20:1122-30