Abstract
This volume is intended to review the methods used to identify biomarkers predictive of cancer responsiveness to immunotherapy. The successful development of clinically actionable biomarkers depends upon three features: (a) their biological role with respect to malignant transformation and tumor progression; (b) the ability to detect them with robust, reliable, and clinically applicable assays; and (c) their prognostic or predictive value, as validated in clinical trials.
Identifying biomarkers that have predictive value for patient selection based on the likelihood of benefiting from anticancer immunotherapy is a lengthy and complex process. To date, few predictive biomarkers for anticancer immunotherapy have been robustly analytically and clinically validated (i.e., PD-L1 expression as measured by IHC assays and microsatellite instability (MSI)/dMMR as measured by PCR or IHC, respectively).
This introductory chapter to this book focuses on scientific and technical aspects relevant to the identification and validation of predictive biomarkers for immunotherapy. We emphasize that methods should address both the biology of the tumor and the tumor microenvironment. Moreover, the identification of biomarkers requires highly sensitive, multiplexed, comprehensive techniques, especially for application in clinical care. Thus, in this chapter, we will define the outstanding questions related to the immune biology of cancer as a base for development of the biomarkers and assays using diverse methodologies. These biomarkers will likely be identified through research that integrates conventional immunological approaches along with high-throughput genomic and proteomic screening and the host immune response of individual patients that relates to individual tumor biology and immune drugs’ mechanism of action.
Checkpoint inhibitor therapy (CIT) is by now an accepted modality of cancer treatment. However, immune resistance is common, and most patients do not benefit from the treatment. The reasons for resistance are diverse, and approaches to circumvent it need to consider genetic, biologic, and environmental factors that affect anticancer immune response. Here, we propose to systematically address fundamental concepts based on the premise that malignant cells orchestrate their surroundings by interacting with innate and adaptive immune sensors. This principle applies to most cancers and governs their evolution in the immune-competent host. Understanding the basic requirement(s) for this evolutionary process will guide biomarker discovery and validation and ultimately guide to effective therapeutic choices. This volume will also discuss novel biomarker approaches aimed at informing an effective assay development from a mechanistic point of view, as well as the clinical implementation (i.e., patient enrichment) for immune therapies.
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Abbreviations
- CDR3:
-
Complementarity determining region 3
- CIT:
-
Checkpoint inhibitor therapy
- FDA:
-
Food and Drug Administration
- FFPE:
-
Formalin-fixed paraffin-embedded
- HLA:
-
Human leukocyte antigen
- ICD:
-
Immunogenic cell death
- ICR:
-
Immunologic constant of rejection
- IFN:
-
Interferon
- IHC:
-
Immunohistochemistry
- IL:
-
Interleukin
- IO:
-
Immune oncology
- MOA:
-
Mechanism of action
- MSI-H/dMMR:
-
Microsatellite instability high/deficient mismatch repair
- PD-L1:
-
Programmed death-ligand 1
- STAT:
-
Signal transducer and activator of transcription
- TCR:
-
T cell receptor
- TILs:
-
Tumor-infiltrating lymphocytes
- TIS:
-
Tumor inflammation signature
- TMB:
-
Tumor mutation burden
- TME:
-
Tumor microenvironment
References
Salk J (1969) Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors, and normal tissue. Ann N Y Acad Sci 164(2):365–380
Gong J, Chehrazi-Raffle A, Reddi S, Salgia R (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6(1):8
Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL et al (2017) Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer 81:116–129
Ascierto PA, Puzanov I, Agarwala SS, Bifulco C, Botti G, Caraco C et al (2018) Perspectives in melanoma: meeting report from the Melanoma Bridge (30 November–2 December, 2017, Naples, Italy). J Transl Med 16(1):207
Ascierto PA, Brugarolas J, Buonaguro L, Butterfield LH, Carbone D, Daniele B et al (2018) Perspectives in immunotherapy: meeting report from the Immunotherapy Bridge (29–30 November, 2017, Naples, Italy). J Immunother Cancer 6(1):69
Memarnejadian A, Meilleur CE, Shaler CR, Khazaie K, Bennink JR, Schell TD et al (2017) PD-1 blockade promotes epitope spreading in anticancer CD8(+) T cell responses by preventing fratricidal death of subdominant clones to relieve immunodomination. J Immunol 199(9):3348–3359
Wang E, Zhao Y, Monaco A, Uccellini L, Kirkwood JM, Spyropoulou-Vlachou M et al (2012) A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon. PLoS One 7(7):e40805
Lu R, Turan T, Samayoa J, Marincola FM (2017) Cancer immune resistance: can theories converge? Emerg Top Life Sci 1(5):411–419
Turan T, Kannan D, Patel M, Barnes MJ, Tanlimco SG, Lu R et al (2018) Immune oncology, immune responsiveness and the theory of everything. J Immunother Cancer 6(1):50
Wang E, Worschech A, Marincola FM (2008) The immunologic constant of rejection. Trends Immunol 29(6):256–262
Orecchioni M, Bedognetti D, Newman L, Fuoco C, Spada F, Hendrickx W et al (2017) Single-cell mass cytometry and transcriptome profiling reveal the impact of graphene on human immune cells. Nat Commun 8(1):1109
Galon J, Angell HK, Bedognetti D, Marincola FM (2013) The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39(1):11–26
Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG et al (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 7:10501
Abd Al Samid M, Chaudhary B, Khaled YS, Ammori BJ, Elkord E (2016) Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients. Oncotarget 7(12):14083–14094
Alinejad V, Dolati S, Motallebnezhad M, Yousefi M (2017) The role of IL17B-IL17RB signaling pathway in breast cancer. Biomed Pharmacother 88:795–803
Munn DH, Bronte V (2016) Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol 39:1–6
Mondanelli G, Ugel S, Grohmann U, Bronte V (2017) The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO. Curr Opin Pharmacol 35:30–39
Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G (2017) Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17(2):97–111
Crittenden MR, Baird J, Friedman D, Savage T, Uhde L, Alice A et al (2016) Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy. Oncotarget 7(48):78653–78666
Hatfield SM, Sitkovsky M (2016) A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1alpha driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol 29:90–96
Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M et al (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 214(3):579–596
Salerno EP, Bedognetti D, Mauldin IS, Deacon DH, Shea SM, Pinczewski J et al (2016) Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk. Oncoimmunology 5(12):e1240857
Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523(7559):231–235
Daragmeh J, Barriah W, Saad B, Zaid H (2016) Analysis of PI3K pathway components in human cancers. Oncol Lett 11(4):2913–2918
De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH et al (2016) Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature 539(7629):443–447
Karlsson E, Veenstra C, Emin S, Dutta C, Perez-Tenorio G, Nordenskjold B et al (2015) Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Res Treat 153(1):31–40
Hendrickx W, Simeone I, Anjum S, Mokrab Y, Bertucci F, Finetti P et al (2017) Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology 6(2):e1253654
Turan T, Kannan D, Patel M, Matthew Barnes J, Tanlimco SG, Lu R et al (2018) Immune oncology, immune responsiveness and the theory of everything. J Immunother Cancer 6(1):50
Mantovani A, Romero P, Palucka AK, Marincola FM (2008) Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371(9614):771–783
Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10
Rossi J, Paczkowski P, Shen YW, Morse K, Flynn B, Kaiser A et al (2018) Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 132(8):804–814
Labi V, Erlacher M (2015) How cell death shapes cancer. Cell Death Dis 6:e1675
Palmieri G, Colombino M, Cossu A, Marchetti A, Botti G, Ascierto PA (2017) Genetic instability and increased mutational load: which diagnostic tool best direct patients with cancer to immunotherapy? J Transl Med 15(1):17
Ward JP, Gubin MM, Schreiber RD (2016) The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv Immunol 130:25–74
Fuchs EJ, Matzinger P (1996) Is cancer dangerous to the immune system? Semin Immunol 8(5):271–280
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR et al (2017) IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127(8):2930–2940
Weiss GR, Grosh WW, Chianese-Bullock KA, Zhao Y, Liu H, Slingluff CL Jr et al (2011) Molecular insights on the peripheral and intratumoral effects of systemic high-dose rIL-2 (aldesleukin) administration for the treatment of metastatic melanoma. Clin Cancer Res 17(23):7440–7450
Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME et al (2013) CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. Br J Cancer 109(9):2412–2423
Wang E, Miller LD, Ohnmacht GA, Mocellin S, Perez-Diez A, Petersen D et al (2002) Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness. Cancer Res 62(13):3581–3586
Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X et al (2018) Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 17(1):129
Critchley-Thorne RJ, Simons DL, Yan N, Miyahira AK, Dirbas FM, Johnson DL et al (2009) Impaired interferon signaling is a common immune defect in human cancer. Proc Natl Acad Sci U S A 106(22):9010–9015
Liu Q, Tomei S, Ascierto ML, De Giorgi V, Bedognetti D, Dai C et al (2014) Melanoma NOS1 expression promotes dysfunctional IFN signaling. J Clin Invest 124(5):2147–2159
Panelli MC, Wang E, Phan G, Puhlmann M, Miller L, Ohnmacht GA et al (2002) Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 3(7):R35
Ohnmacht GA, Wang E, Mocellin S, Abati A, Filie A, Fetsch P et al (2001) Short-term kinetics of tumor antigen expression in response to vaccination. J Immunol 167(3):1809–1820
Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273
Hicklin DJ, Marincola FM, Ferrone S (1999) HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 5(4):178–186
Ohnmacht GA, Marincola FM (2000) Heterogeneity in expression of human leukocyte antigens and melanoma-associated antigens in advanced melanoma. J Cell Physiol 182(3):332–338
Della Corte CM, Byers LA (2019) Evading the STING: LKB1 loss leads to STING silencing and immune escape in KRAS-mutant lung cancers. Cancer Discov 9(1):16–18
Della Corte CM, Gay CM, Byers LA (2019) Beyond chemotherapy: emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era. Cancer 125(4):496–498
Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin H et al (2016) CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun 7:12320
Lam TK, Shao S, Zhao Y, Marincola F, Pesatori A, Bertazzi PA et al (2012) Influence of quercetin-rich food intake on microRNA expression in lung cancer tissues. Cancer Epidemiol Biomark Prev 21(12):2176–2184
Gutierrez-Arcelus M, Rich SS, Raychaudhuri S (2016) Autoimmune diseases—connecting risk alleles with molecular traits of the immune system. Nat Rev Genet 17(3):160–174
Soldati L, Di Renzo L, Jirillo E, Ascierto PA, Marincola FM, De Lorenzo A (2018) The influence of diet on anti-cancer immune responsiveness. J Transl Med 16(1):75
Roy S, Trinchieri G (2017) Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17(5):271–285
Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K et al (2017) Influence of diet on the gut microbiome and implications for human health. J Transl Med 15(1):73
Masucci GV, Cesano A, Eggermont A, Fox BA, Wang E, Marincola FM et al (2017) The need for a network to establish and validate predictive biomarkers in cancer immunotherapy. J Transl Med 15(1):223
Dobbin KK, Cesano A, Alvarez J, Hawtin R, Janetzki S, Kirsch I et al (2016) Validation of biomarkers to predict response to immunotherapy in cancer: volume II—clinical validation and regulatory considerations. J Immunother Cancer 4:77
Taube JM, Galon J, Sholl LM, Rodig SJ, Cottrell TR, Giraldo NA et al (2018) Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol 31(2):214–234
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH et al (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20(19):5064–5074
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567
Wang Q, Liu F, Liu L (2017) Prognostic significance of PD-L1 in solid tumor: an updated meta-analysis. Medicine 96(18):e6369
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571
Giraldo NA, Nguyen P, Engle EL, Kaunitz GJ, Cottrell TR, Berry S et al (2018) Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab. J Immunother Cancer 6(1):99
Halse H, Colebatch AJ, Petrone P, Henderson MA, Mills JK, Snow H et al (2018) Multiplex immunohistochemistry accurately defines the immune context of metastatic melanoma. Sci Rep 8(1):11158
Tsujikawa T, Kumar S, Borkar RN, Azimi V, Thibault G, Chang YH et al (2017) Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep 19(1):203–217
Vanderwalde A, Spetzler D, Xiao N, Gatalica Z, Marshall J (2018) Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med 7(3):746–756
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520
Fabrizio DA, George TJ Jr, Dunne RF, Frampton G, Sun J, Gowen K et al (2018) Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition. J Gastrointest Oncol 9(4):610–617
Salem ME, Puccini A, Grothey A, Raghavan D, Goldberg RM, Xiu J et al (2018) Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res 16(5):805–812
Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199
Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X et al (2016) Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res 4(11):959–967
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27(8):1386–1422
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J et al (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31(11):1023–1031
Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V et al (2017) Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 16(11):2598–2608
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351(6280):1463–1469
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128
Saeterdal I, Bjorheim J, Lislerud K, Gjertsen MK, Bukholm IK, Olsen OC et al (2001) Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci U S A 98(23):13255–13260
Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S et al (2017) Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 168(3):542
Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS et al (2017) Tumor and microenvironment evolution during immunotherapy with Nivolumab. Cell 171(4):934–49.e15
Cesano A (2015) nCounter((R)) PanCancer immune profiling panel (NanoString Technologies, Inc., Seattle, WA). J Immunother Cancer 3:42
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301
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Cesano, A., Marincola, F.M., Thurin, M. (2020). Status of Immune Oncology: Challenges and Opportunities. In: Thurin, M., Cesano, A., Marincola, F. (eds) Biomarkers for Immunotherapy of Cancer. Methods in Molecular Biology, vol 2055. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9773-2_1
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