Table 1.

Summary of biomarkers associated with cancer immunotherapy biomarkers.

Biomarkers	Clinical correlation	References
T cell immunoreceptor with Ig and ITIM domains (TIGIT)	•Increased TIGIT/CD226 expression ratio associated with poor survival in AML, BGM, melanoma	•Fourcade J, Sun Z, Chauvin JM, et al. CD226 opposes TIGIT to disrupt Tregs in melanoma[published online ahead of print, 2018 Jul 25]. JCI Insight. 2018;3(14):e121157.
CTLA-4 blockade
Tumor infiltrating lymphocytes (TIL)	•Presence of TIL associated with positive clinical response in melanoma patients	•Ruffini E, Asioli S, Filosso PL, et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg 2009; 87: 365–371.
	•Increase in granzyme B, a surrogate of CD8 effector function, associated with positive clinical response in melanoma patients
Absolute lymphocyte count (ALC) and absolute neutrophil count (ANC)	•Increased neutrophil-to-lymphocyte ratio (NLR) prior to anti-CTLA-4 therapy associated with poor prognosis	•Zaragoza J, Caille A, Beneton N, et al. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br. J. Dermatol., 174;2016:146–151.
	•Neutrophilia and eosinophilia associated with increased risk of colitis in anti-CTLA-4 therapy
		•Maleki Vareki S, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev. Oncol Hematol. 2017;116:116–124.
Inducible co-stimulator (ICOS)	•Increase in CD4+ICOS+ T cell expression associated with improved survival outcomes	•Manson G, Norwood J, Marabelle A, et al. Biomarkers associated with checkpoint inhibitors. Annals of Oncology, Oxford University Press (OUP), 2016; 27 (7):1199–1206.
T cell repertoire (TCR)	•Increased TCR diversity associated with decreased rates of overall survival	•Maleki Vareki S, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev. Oncol Hematol. 2017;116:116–124.
Tumor associated antigens (TAA)	•NY-ESO-1 associated with improved clinical outcomes in small cohorts of melanoma patients	•Weide B, Zelba H, Derhovanessian E, et al. Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis. J Clin Oncol. 2012;30(15):1835–41.
	•Melan-A associated with improved survival outcomes in melanoma and prostate cancer patients
Myeloid derived suppressor cells (MDSC)	•Decreased MDSC frequency associated with improved survival outcomes	•Meyer C, Cagnon L, Costa-Nunes CM, et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 2014;63(3):247–57.
Regulatory T cells (Treg)	•Soluble CD25 associated with poor clinical outcome	•deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res. 2012;18(11):3022–9.
		•Hannani D, Vétizou M, Enot D, et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Research. 2015;25(2):208–224.
	•CD4+FOXP3+CD25hi associated with poor clinical outcome
	•No consensus on which Treg subset should be monitored in anti-CTLA-4 therapy
Indoleamine 2,3-Dioxygenase (IDO)	•Increased IDO expression associated with improved clinical outcomes	•Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011;9:204.
Microbiome profile	•Animal models transplanted with either Bacteroides species or Bifidobacterium exhibited improved T cell activation and favorable response to anti-CTLA-4 therapy	•Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science (New York, NY). 2015;350(6264):1079–1084.
PD-1/PD-L1 blockade
PD-L1 expression	•PD-L1 expression is currently the most commonly used predictive biomarker in anti-PD-1 therapy	•Patel, SP, Kurzrock, R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther April 12,015 (14) (4) 847–856.
	•Increased PD-L1 expression is associated with improved response
		•Brody, R, Zhang, Y, Ballas, M, et al. PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer. 2017 Oct;112:200–215.
ALC and ANC	•Further studies needed to determine the predictive or prognostic value in anti-PD-1 therapy	•Lin G, Liu Y, Li S, et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget. 2016;7:50963–50971.
TIL	•Increase in granzyme B, a surrogate of CD8 effector function, associated with positive clinical response in melanoma patients	•Ruffini E, Asioli S, Filosso PL, et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg 2009; 87: 365–371.
	•Further studies needed to determine the predictive or prognostic value of TIL for other malignancies
Peripheral blood markers	•Overexpression of IFN-γ associated with clinical response in melanoma, no association reported in non-small cell lung carcinoma (NSCLC) or renal cell carcinoma (RCC)	•Martens A, Wistuba-Hamprecht K, Foppen MG, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clinical cancer research: an official journal of the American Association for Cancer Research. 2016;22(12):2908–2918.
		•Krieg C, Nowicka M, Guglietta S, et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med. 2018;(2):144–153.
	•No association with inducible T-cell alpha chemo-attractant (ITAC) and IL-18 production and clinical response
	•Presence of classical monocytes (CD14+CD16−) associated with higher amounts of ICAM-1 and HLA-DR, which are both associated with positive clinical response
IDO	•Increased IDO expression associated with improved clinical outcomes in melanoma, but not NSCLC or RCC	•McNamara MJ, Hilgart-Martiszus I, Barragan Echenique DM, et al. Interferon-gamma production by peripheral lymphocytes predicts survival of tumor-Bearing mice receiving dual PD-1/CTLA-4 blockade. Cancer Immunol. Res. 2016;21:650–657.
	•Combination of anti-PD-1 and anti-IDO-1 therapy did not show improved progression-free survival in metastatic melanoma patients
Mutational load	•High mutational load associated with positive clinical response in melanoma, NSCLC, bladder cancer, and colorectal cancer	•Rooney MS, Shukla SA, Wu CJ, et al. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160: 48–61.
	•High mutational load associated with higher progression-free and overall survival rates in NSCLC and SCLC patients receiving combination nivolumab+ipilimumab
		•Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell. 2018 May 14;33(5):853–861.e4.
Mismatch repair deficiency (mmrd)	•MMRD increases immunogenicity in hereditary non-polyposis colorectal cancer (HNPCC)	•Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-Repair deficiency. N. Engl. J. Med. 2015;372:2509–2520.
		•Lee V, Murphy A, Le DT, Diaz Jr., LA. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist. 2016;21:1200–1211.
TCR	•Increased T cell clonality (less diversity) associated with positive clinical response	•Maleki Vareki S, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev. Oncol Hematol. 2017;116:116–124.
Microbiome profile	•The presence of A. muciniphila commensal is associated with favorable outcome in NSCLC and RCC	•Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–97.
		•Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.
		•Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–108.
		•Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018; 2;359(6375):582–587.
	•High concentrations of Ruminococcaceae/Faecalibacterium are associated with enhanced anti-tumor immune responses in melanoma patients undergoing anti-PD-1 therapy
	•High concentrations of Enterococcus faecium, Collinsella aerofaciens, Bifidobacterium adolescentis, Klebsiella pneumoniae, Veillonella parvula, Parabacteroides merdae, Lactobacillus sp., and Bifidobacterium longum commensal are associated with positive response to anti-PD-1 therapy
	•The presence of Ruminococcus obeum and Roseburia intestinalis commensal associated with poor response to anti-PD-1 therapy
Human leukocyte antigen class I (HLA—I) genotype	•HLA-I loci heterozygosity associated with improved survival than homozygosity for one or more HLA-I genes	•Snary, D. Barnstable, CJ, Bodmer, WF, et al. Molecular structure of human histocompatibility antigens: The HLA-C series. Eur. J. Immunol. 1977;7:580–585.
	•HLA-B homozygosity and loss of heterozogosity (LOH) at HLA-I associated with decreased overall survival
	•HLA-I homozygosity and LOH at HLA-I associated with decreased response to immunotherapy
		•Marsh, SG, Parham, P, Barber, LD. The HLA Factsbook. Academic Press, 1999.
	•HLA-I homozygosity and low mutational load associated with decreased overall survival
		•Bobisse S, Foukas PG, Coukos G, Harari A. Neoantigen-based cancer immunotherapy. Annals of Translational Medicine. 2016;4(14):262.
Mutational load and increased neoantigen (neoAg) frequency	•Presence of mutational load and increased neoAg frequency associated with clinical response in melanoma and NSCLC undergoing both anti-CTLA-4 and anti-PD-1 therapies	•Maleki Vareki S, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev. Oncol Hematol. 2017;116:116–124.
NeoAg-reactive CD4+ and CD8+ T cells	•Presence of neoAg-reactive CD4+ and CD8+ T cells associated with improved clinical response	•Bobisse S, Foukas PG, Coukos G, Harari A. Neoantigen-based cancer immunotherapy. Annals of Translational Medicine. 2016;4(14):262.
NK cell frequency	•Increased NK cell frequency is a positive prognostic factor in patients with metastatic prostate cancer, colorectal carcinoma, and melanoma	•Böttcher JP, Bonavita E, Chakravarty P, et al. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell. 2018;172(5):1022–1037.e14.
Ki-67 Expression on PD-1+ CD8 T Cells	•Increased Ki-67 expression on PD-1+ CD8 T cells is a positive prognostic factor for treatment response	•Kamphorst AO, Pillai RN, Yang S, et al. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A. 2017;114(19):4993–4998.
Signatures of T cell dysfunction and exclusion (TIDE)	•High T cell dysfunction is a predictive biomarker for poor immunotherapy treatment response	•Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018 Oct;24(10):1550–1558.
	•SERPINB9 is a predictive biomarker for poor immunotherapy treatment response
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy
Polyfunctional CAR T Cells	•TNF-α+IFN-γ+ polyfunctional T cells delay tumor relapse	•Lin Y, Gallardo HF, Ku GY, et al. Optimization and validation of a robust human T-cell culture method for monitoring phenotypic and polyfunctional antigen-specific CD4 and CD8 T-cell responses. Cytotherapy. 2009;11(7):912–22.
IL-6/STAT3	•Associated with CAR T cell expansion and complete response in chronic lymphocytic leukemia (CLL)	•Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018.
Upregulation of programs involved in effector differentiation, glycolysis, exhaustion, and apoptosis	•Associated with no response to CAR T cell therapy in CLL	•Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018.