Peripheral immune biomarkers for immune checkpoint inhibition of solid tumours

Abstract

	•Peripheral immune biomarkers are critical for improved prediction and prognostication of clinical outcomes for patients with solid tumours treated with immune checkpoint inhibition.
	•Candidate peripheral biomarkers, such as cytokines, soluble factors, and immune cells, have potential as biomarkers to guide immunotherapy of solid tumours.
	•Multiple peripheral immune parameters may be integrated to improve prediction and prognostication.
	•The potential of peripheral immune biomarkers to guide immunotherapy of solid tumours requires critical work in biomarker discovery, validation, and standardization.

Keywords

biomarkers / immunotherapy / peripheral blood / tumour microenvironment

References

[1] HaslamA, GillJ, PrasadV. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open. 2020;3:e200423.

[2] GoossensN, Nakagawa S, SunX, HoshidaY. Cancer biomarker discovery and validation. Transl Cancer Res. 2015;4:256-269.

[3] SankarK, YeJC, LiZ, ZhengL, SongW, Hu-Lieskovan S. The role of biomarkers in personalized immunotherapy. Biomark Res. 2022;10:32.

[4] BrummelK, Eerkens AL, De BruynM, NijmanHW. Tumour-infiltrating lymphocytes: from prognosis to treatment selection. Br J Cancer. 2023;128:451-458.

[5] CabritaR, LaussM, SannaA, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577:561-565.

[6] SchumacherTN, Thommen DS. Tertiary lymphoid structures in cancer. Science. 2022;375:eabf9419.

[7] Hiam-GalvezKJ, AllenBM, SpitzerMH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21:345-359.

[8] ZahranAM, RayanA, ZahranZAM, et al. Overexpression of PD-1 and CD39 in tumor-infiltrating lymphocytes compared with peripheral blood lymphocytes in triple-negative breast cancer. PLoS One. 2022;17:e0262650.

[9] SteeleNG, Carpenter ES, KempSB, et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat Cancer. 2020;1:1097-1112.

[10] SunK, XuR, MaF, et al. scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nat Commun. 2022;13:4943.

[11] ZhengL, QinS, SiW, et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science. 2021;374:abe6474.

[12] LiT, ZhaoL, YangY, et al. T cells expanded from PD-1(+) peripheral blood lymphocytes share more clones with paired tumor-infiltrating lymphocytes. Cancer Res. 2021;81:2184-2194.

[13] WangL, SimonsDL, LuX, et al. Connecting blood and intratumoral T(reg) cell activity in predicting future relapse in breast cancer. Nat Immunol. 2019;20:1220-1230.

[14] LiyanageUK, MooreTT, JooH-Gu, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756-2761.

[15] WallinJJ, Bendell JC, FunkeR, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.

[16] AbdelfatahE, LongMD, KajiharaR, et al. Predictive and prognostic implications of circulating CX3CR1(+) CD8(+) T cells in non-small cell lung cancer patients treated with chemo-immunotherapy. Cancer Res Commun. 2023;3:510-520.

[17] StraussJ, HeeryCR, KimJW, et al. First-in-human phase I trial of a tumor-targeted cytokine (NHS-IL12) in subjects with metastatic solid tumors. Clin Cancer Res. 2019;25:99-109.

[18] van den EndeT, et al. Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with neoadjuvant PD-L1 checkpoint inhibition. Oncoimmunology. 2023;12:2233403.

[19] RuanD-Y, ChenY-X, WeiX-Li, et al. Elevated peripheral blood neutrophil-to-lymphocyte ratio is associated with an immunosuppressive tumour microenvironment and decreased benefit of PD-1 antibody in advanced gastric cancer. Gastroenterol Rep (Oxf). 2021;9:560-570.

[20] YoshidaT, OheC, ItoK, et al. Clinical and molecular correlates of response to immune checkpoint blockade in urothelial carcinoma with liver metastasis. Cancer Immunol Immunother. 2022;71:2815-2828.

[21] GocherAM, Workman CJ, VignaliDAA. Interferon-γ: teammate or opponent in the tumour microenvironment? Nat Rev Immunol. 2022;22:158-172.

[22] WangL, SimonsDL, LuX, et al. Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes. EBioMedicine. 2020;52:102631.

[23] GriffithsJI, WalletP, PfliegerLT, et al. Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy. Proc Natl Acad Sci U S A. 2020;117:16072-16082.

[24] ToneyNJ, SchlomJ, DonahueRN. Phosphoflow cytometry to assess cytokine signaling pathways in peripheral immune cells: potential for inferring immune cell function and treatment response in patients with solid tumors. J Exp Clin Cancer Res. 2023;42:247.

[25] ChenC, YinH, ZhangYu, Chen H, XuJ, RenL. Plasma D-dimer and interleukin-6 are associated with treatment response and progression-free survival in advanced NSCLC patients on anti-PD-1 therapy. Cancer Med. 2023;12:15831-15840.

[26] LiuC, YangL, XuH, et al. Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer. BMC Med. 2022;20:187.

[27] KangDaH, ParkC-K, ChungC, et al. Baseline serum Interleukin-6 levels predict the response of patients with advanced non-small cell lung cancer to PD-1/PD-L1 inhibitors. Immune Netw. 2020;20:e27.

[28] Hardy-WerbinM, RochaP, ArpiO, et al. Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer. Oncoimmunology. 2019;8:e1593810.

[29] YangH, KangB, HaY, et al. High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma. JHEP Rep. 2023;5:100672.

[30] SangYB, YangH, LeeWS, et al. High serum levels of IL-6 predict poor responses in patients treated with pembrolizumab plus axitinib for advanced renal cell carcinoma. Cancers (Basel). 2022;14:5985.

[31] MyojinY, KodamaT, SakamoriR, et al. Interleukin-6 is a circulating prognostic biomarker for hepatocellular carcinoma patients treated with combined immunotherapy. Cancers (Basel). 2022;14.

[32] KeeganA, Ricciuti B, GardenP, et al. Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC. J Immunother Cancer. 2020;8:e000678.

[33] MooreKW, De Waal Malefyt R, CoffmanRL, O’garraA. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.

[34] KimY, YangH, LeeWS, et al. High levels of baseline serum IL-10 are associated with reduced clinical benefit from first-line immune checkpoint inhibitor therapy in advanced renal cell carcinoma. J Cancer. 2023;14:935-942.

[35] MaoX-C, YangC-C, YangYa-F, et al. Peripheral cytokine levels as novel predictors of survival in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol. 2022;13:884592.

[36] DavidJM, Dominguez C, HamiltonDH, PalenaC. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel). 2016;4:22.

[37] YuenKC, LiuLi-F, GuptaV, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat Med. 2020;26:693-698.

[38] SchalperKA, Carleton M, ZhouM, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat Med. 2020;26:688-692.

[39] GuD, AoX, YangYu, Chen Z, XuX. Soluble immune checkpoints in cancer: production, function and biological significance. J Immunother Cancer. 2018;6:32.

[40] ChakrabartiR, KapseB, MukherjeeG. Soluble immune checkpoint molecules: serum markers for cancer diagnosis and prognosis. Cancer Rep (Hoboken). 2019;2:e1160.

[41] MurakamiS, Shibaki R, MatsumotoY, et al. Association between serum level soluble programmed cell death ligand 1 and prognosis in patients with non-small cell lung cancer treated with anti-PD-1 antibody. Thorac Cancer. 2020;11:3585-3595.

[42] OkumaY, WakuiH, UtsumiH, et al. Soluble programmed cell death ligand 1 as a novel biomarker for nivolumab therapy for non-small-cell lung cancer. Clin Lung Cancer. 2018;19:410-417.e411

[43] KawakamiH, Sunakawa Yu, InoueE, et al. Soluble programmed cell death ligand 1 predicts prognosis for gastric cancer patients treated with nivolumab: blood-based biomarker analysis for the DELIVER trial. Eur J Cancer. 2023;184:10-20.

[44] Tiako MeyoM, Jouinot A, Giroux-LeprieurE, et al. Predictive value of soluble PD-1, PD-L1, VEGFA, CD40 ligand and CD44 for nivolumab therapy in advanced non-small cell lung cancer: a case-control study. Cancers (Basel). 2020;12:473.

[45] HimuroH, Nakahara Y, IgarashiY, et al. Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors. Cancer Immunol Immunother. 2023;72:2829-2840.

[46] WakitaN, HinataN, BandoY, et al. prognostic value of serum soluble PD-L1 in metastatic renal cell carcinoma patients treated with nivolumab. Anticancer Res. 2023;43:841-847.

[47] CullenSP, MartinSJ. Mechanisms of granule-dependent killing. Cell Death Differ. 2008;15:251-262.

[48] HurkmansDP, BasakEA, SchepersN, et al. Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer. J Immunother Cancer. 2020;8:e000586.

[49] ShaoC, ZhuC, ZhuY, et al. Decrease of peripheral blood mucosal-associated invariant T cells and impaired serum Granzyme-B production in patients with gastric cancer. Cell Biosci. 2021;11(1):12.

[50] ToneyNJ, Gatti-Mays ME, TscherniaNP, et al. Immune correlates with response in patients with metastatic solid tumors treated with a tumor targeting immunocytokine NHS-IL 12. Int Immunopharmacol. 2023;116:109736.

[51] GrosA, TranE, ParkhurstMR, et al. Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes. J Clin Invest. 2019;129(11):4992-5004.

[52] KimKH, ChoJ, KuBoMi, et al. The first-week proliferative response of peripheral blood PD-1(+)CD8(+) T cells predicts the response to anti-PD-1 therapy in solid tumors. Clin Cancer Res. 2019;25:2144-2154.

[53] HopkinsAC, Yarchoan M, DurhamJN, et al. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight. 2018;3(13):e122092.

[54] HoganSA, Courtier A, ChengPF, et al. Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against Melanoma. Cancer Immunol Res. 2019;7:77-85.

[55] FairfaxBP, TaylorCA, WatsonRA, et al. Peripheral CD8(+) T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. Nat Med. 2020;26:193-199.

[56] HanJ, DuanJ, BaiH, et al. TCR repertoire diversity of peripheral PD-1(+)CD8(+) T cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer. Cancer Immunol Res. 2020;8:146-154.

[57] KimCG, KimKH, PyoK-H, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol. 2019;30:1104-1113.

[58] SimonS, Voillet V, VignardV, et al. PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy. J Immunother Cancer. 2020;8:e001631.

[59] ShenR, PostowMA, AdamowM, et al. LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade. Sci Transl Med. 2021;13:eabf5107.

[60] CirilloA, Zizzari IG, BotticelliA, et al. Circulating CD137(+) T cell levels are correlated with response to pembrolizumab treatment in advanced head and neck cancer patients. Int J Mol Sci. 2023;24:7114.

[61] FerraraR, Naigeon M, AuclinE, et al. Circulating T-cell immunosenescence in patients with advanced non-small cell lung cancer treated with single-agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res. 2021;27:492-503.

[62] YamauchiT, HokiT, ObaT, et al. T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors. Nat Commun. 2021;12(1):1402.

[63] KagamuH, KitanoS, YamaguchiOu, et al. CD4(+) T-cell immunity in the peripheral blood correlates with response to anti-PD-1 therapy. Cancer Immunol Res. 2020;8:334-344.

[64] KangDaH, ChungC, SunP, et al. Circulating regulatory T cells predict efficacy and atypical responses in lung cancer patients treated with PD-1/PD-L1 inhibitors. Cancer Immunol Immunother. 2022;71:579-588.

[65] HelminkBA, ReddySM, GaoJ, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577:549-555.

[66] KimSS, SumnerWA, MiyauchiS, Cohen EEW, CalifanoJA, SharabiAB. Role of B cells in responses to checkpoint blockade immunotherapy and overall survival of cancer patients. Clin Cancer Res. 2021;27:6075-6082.

[67] YuanS, LiuY, TillB, Song Y, WangZ. Pretreatment peripheral B cells are associated with tumor response to anti-PD-1-based immunotherapy. Front Immunol. 2020;11:563653.

[68] XiaL, GuoL, KangJ, et al. Predictable roles of peripheral IgM memory b cells for the responses to anti-PD-1 monotherapy against advanced non-small cell lung cancer. Front Immunol. 2021;12:759217.

[69] BarthDA, Stanzer S, SpiegelbergJA, et al. Patterns of peripheral blood B-cell subtypes are associated with treatment response in patients treated with immune checkpoint inhibitors: a prospective longitudinal pan-cancer study. Front Immunol. 2022;13:840207.

[70] LaoJ, XuH, LiangZ, et al. Peripheral changes in T cells predict efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer. Immunobiology. 2023;228:152391.

[71] Lo RussoG, et al. PEOPLE (NTC03447678), a phase II trial to test pembrolizumab as first-line treatment in patients with advanced NSCLC with PD-L1 <50%: a multiomics analysis. J Immunother Cancer. 2023;11:e006833.

[72] XieQu, HuC, LuoC. The alterations in peripheral lymphocyte subsets predict the efficacy and prognosis of immune checkpoint inhibitors in hepatocellular carcinoma. J Cancer. 2023;14:2946-2955.

[73] Gascón-RuizM, Ramírez-Labrada A, LastraR, et al. A subset of PD-1-expressing CD56(bright) NK cells identifies patients with good response to immune checkpoint inhibitors in lung cancer. Cancers (Basel). 2023;15:329.

[74] ZhouJ, ChuX, ZhaoJ, et al. Full spectrum flow cytometry-powered comprehensive analysis of PBMC as biomarkers for immunotherapy in NSCLC with EGFR-TKI resistance. Biol Proced Online. 2023;25(1):21.

[75] EngblomC, Pfirschke C, PittetMJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer. 2016;16:447-462.

[76] HedrickCC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted. Nat Rev Immunol. 2022;22:173-187.

[77] ZhouJG, Donaubauer AJ, FreyB, et al. Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors. J Immunother Cancer. 2021;9(2):e001845.

[78] ShangJ, HanX, ZhaH, et al. Systemic immune-inflammation index and changes of neutrophil-lymphocyte ratio as prognostic biomarkers for patients with pancreatic cancer treated with immune checkpoint blockade. Front Oncol. 2021;11:585271.

[79] PanC, WuQV, VoutsinasJ, et al. Peripheral lymphocytes and lactate dehydrogenase correlate with response and survival in head and neck cancers treated with immune checkpoint inhibitors. Cancer Med. 2023;12:9384-9391.

[80] RebuzziSE, Signori A, StellatoM, et al. The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: the Delta-Meet-URO analysis. Front Oncol. 2022;12:955501.

[81] GuoY, XiangD, WanJ, YangL, ZhengC. Focus on the dynamics of neutrophil-to-lymphocyte ratio in cancer patients treated with immune checkpoint inhibitors: a meta-analysis and systematic review. Cancers (Basel). 2022;14:5297.

[82] OlingyCE, DinhHQ, HedrickCC. Monocyte heterogeneity and functions in cancer. J Leukoc Biol. 2019;106:309-322.

[83] SoyanoAE, Dholaria B, Marin-AcevedoJA, et al. Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies. J Immunother Cancer. 2018;6:129.

[84] WangXi, ZhangBo, ChenX, et al. Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody. Thorac Cancer. 2019;10:1395-1401.

[85] TsaiYT, Strauss J, ToneyNJ, et al. Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa. J Immunother Cancer. 2022;10(4).

[86] VarayathuH, Sarathy V, ThomasB, et al. Translational relevance of baseline peripheral blood biomarkers to assess the efficacy of anti-programmed cell death 1 use in solid malignancies. J Cancer Res Ther. 2021;17:114-121.

[87] OuyangH, XiaoB, HuangY, Wang Z. Baseline and early changes in the neutrophil-lymphocyte ratio (NLR) predict survival outcomes in advanced colorectal cancer patients treated with immunotherapy. Int Immunopharmacol. 2023;123:110703.

[88] DaL, QuZ, ZhangC, et al. Prognostic value of inflammatory markers and clinical features for survival in advanced or metastatic esophageal squamous cell carcinoma patients receiving anti-programmed death 1 treatment. Front Oncol. 2023;13:1144875.

[89] RiemannD, Schütte W, TurzerS, SeligerB, Möller M. High PD-L1/CD274 expression of monocytes and blood dendritic cells is a risk factor in lung cancer patients undergoing treatment with PD1 inhibitor therapy. Cancers (Basel). 2020;12:2966.

[90] VarricchiG, Galdiero MR, LoffredoS, et al. Eosinophils: the unsung heroes in cancer? Oncoimmunology. 2018;7:e1393134.

[91] WillemsM, Scherpereel A, WasielewskiE, et al. Excess of blood eosinophils prior to therapy correlates with worse prognosis in mesothelioma. Front Immunol. 2023;14:1148798.

[92] CalimanE, Fancelli S, OttanelliC, et al. Absolute eosinophil count predicts clinical outcomes and toxicity in non-small cell lung cancer patients treated with immunotherapy. Cancer Treat Res Commun. 2022;32:100603.

[93] HwangM, Canzoniero JV, RosnerS, et al. Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy. J Immunother Cancer. 2022;10(6):e004688.

[94] TuckerMD, BrownLC, ChenYu-W, et al. Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma. Biomark Res. 2021;9:80.

[95] ChenYu-W, TuckerMD, BrownLC, et al. The association between a decrease in on-treatment neutrophil-to-eosinophil ratio (NER) at week 6 after ipilimumab plus nivolumab initiation and improved clinical outcomes in metastatic renal cell carcinoma. Cancers (Basel). 2022;14:3830.

[96] WculekSK, CuetoFJ, MujalAM, Melero I, KrummelMF, SanchoD. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20:7-24.

[97] MöllerM, TurzerS, SchütteW, SeligerB, Riemann D. Blood immune cell biomarkers in patient with lung cancer undergoing treatment with checkpoint blockade. J Immunother. 2020;43:57-66.

[98] GabrilovichDI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162-174.

[99] KohJ, KimY, LeeKY, et al. MDSC subtypes and CD39 expression on CD8(+) T cells predict the efficacy of anti-PD-1 immunotherapy in patients with advanced NSCLC. Eur J Immunol. 2020;50:1810-1819.

[100] SantegoetsSJ, StamAG, LougheedSM, et al. Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab. J Immunother Cancer. 2014;2:31.

[101] FarsaciB, Donahue RN, GrengaI, et al. Analyses of pretherapy peripheral immunoscore and response to vaccine therapy. Cancer Immunol Res. 2016;4:755-765.

[102] LynceF, MainorC, DonahueRN, et al. Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study. Nat Commun. 2024;15:2691.

[103] MazzaschiG, MinariR, ZeccaA, et al. Soluble PD-L1 and circulating CD8+PD-1+ and NK cells enclose a prognostic and predictive immune effector score in immunotherapy treated NSCLC patients. Lung Cancer. 2020;148:1-11.

[104] OuF-S, Michiels S, ShyrYu, AdjeiAA, ObergAL. Biomarker discovery and validation: statistical considerations. J Thorac Oncol. 2021;16:537-545.

[105] MasucciGV, CesanoA, HawtinR, et al. Validation of biomarkers to predict response to immunotherapy in cancer: volume I—pre-analytical and analytical validation. J Immunother Cancer. 2016;4:76.

[106] DobbinKK, CesanoA, AlvarezJ, et al. Validation of biomarkers to predict response to immunotherapy in cancer: volume II—clinical validation and regulatory considerations. J Immunother Cancer. 2016;4:77.

RIGHTS & PERMISSIONS

Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.