Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Abstract

Immunotherapy has become the fourth cancer therapy after surgery, chemotherapy, and radiotherapy. In particular, immune checkpoint inhibitors are proved to be unprecedentedly in increasing the overall survival rates of patients with refractory cancers, such as advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. However, inhibitor therapies are only effective in a small proportion of patients with problems, such as side effects and high costs. Therefore, doctors urgently need reliable predictive biomarkers for checkpoint inhibitor therapies to choose the optimal therapies. Here, we review the biomarkers that can serve as potential predictors of the outcomes of immune checkpoint inhibitor treatment, including tumor-specific profiles and tumor microenvironment evaluation and other factors.

Keywords

immune checkpoint / companion diagnosis / PD-L1 / tumor mutation burden / immune score

References

[1] Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627–1639

[2] Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2): 123–135

[3] Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372(21): 2018–2028

[4] Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23–34

[5] Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4): 320–330

[6] Reck M. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy 2018; 10(2): 93–105

[7] Tony Mok YLW, Watson PA, Zhang J, Rangwala RA, Lopes G. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015; 33(15_suppl): TPS8105

[8] Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O’Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378(22): 2093–2104

[9] Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378(14): 1277–1290

[10] Márquez-Rodas I, Cerezuela P, Soria A, Berrocal A, Riso A, González-Cao M, Martín-Algarra S. Immune checkpoint inhibitors: therapeutic advances in melanoma. Ann Transl Med 2015; 3(18): 267

[11] Lovell RA, Schaeffer DJ, Hooser SB,  Haschek WM,  Dahlem AM,  Carmichael WW,  Beasley VR. Toxicity of intraperitoneal doses of microcystin-LR in two strains of male mice. J Environ Pathol Toxicol Oncol 1989; 9(3): 221–237

[12] Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015; 33(17): 1889–1894

[13] Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16(4): 375–384

[14] Taube JM, Young GD, McMiller TL,  McMiller TL, Chen SM, Salas JT,  Pritchard TS,  Xu HY,  Meeker AK,  Fan JH,  Cheadle C,  Berger AE,  Pardoll DM, Topalian SL. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015; 21(17): 3969–3976

[15] Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563–567

[16] Taube JM, Klein A, Brahmer JR, Xu HY, Pan XY, Kim JH, Chen LP, Pardoll DM,Topalian SL, Anders RA. 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 2014; 20(19): 5064–5074

[17] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26): 2443–2454

[18] Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19): 1803–1813

[19] Lim JS, Sundar R, Chénard-Poirier M, Lopez J, Yap TA. Emerging biomarkers for PD-1 pathway cancer therapy. Biomarkers Med 2017; 11(1): 53–67

[20] Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012; 4(127): 127ra37

[21] Feng Z, Puri S, Moudgil T, Wood W, Hoyt CC, Wang C, Urba WJ, Curti BD, Bifulco CB, Fox BA. Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma. J Immunother Cancer 2015; 3(1): 47

[22] Stack EC, Foukas PG, Lee PP. Multiplexed tissue biomarker imaging. J Immunother Cancer 2016; 4(1): 9

[23] Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015; 14(4): 847–856

[24] Sun WY, Lee YK, Koo JS. Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies. J Transl Med 2016; 14(1): 173

[25] Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515(7528): 568–571

[26] Marianne J. Ratcliffe AS, Midha A, Barker C, Scorer P, Walker J. A comparative study of PD-L1 diagnostic assays and the classification of patients as PD-L1 positive and PD-L1 negative. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16–20; New Orleans, LA. Philadelphia (PA): AACR. Cancer Res 2016; 76(14 Suppl): Abstract nr LB-094

[27] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509–2520

[28] Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348(6230): 124–128

[29] Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499(7457): 214–218

[30] Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371(23): 2189–2199

[31] Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387(10031): 1909–1920

[32] Spencer KR, Wang J, Silk AW, Ganesan S, Kaufman HL, Mehnert JM. Biomarkers for immunotherapy: current developments and challenges. Am Soc Clin Oncol Educ Book 2016; 35(36): e493–e503

[33] McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016; 351(6280): 1463–1469

[34] Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J, Ozkan E, Davis MM, Wucherpfennig KW, Garcia KC. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 2014; 157(5): 1073–1087

[35] Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MHG, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 2015; 350(6257): 207–211

[36] Drake JW, Charlesworth B, Charlesworth D, Crow JF. Rates of spontaneous mutation. Genetics 1998; 148(4): 1667–1686

[37] Kunkel TA, Bebenek K. DNA replication fidelity. Annu Rev Biochem 2000; 69(1): 497–529

[38] Preston BD, Albertson TM, Herr AJ. DNA replication fidelity and cancer. Semin Cancer Biol 2010; 20(5): 281–293

[39] Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409–413

[40] Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, Kelley MC, Sosman JA, Johnson DB, Ribas A, Lo RS. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016; 165(1): 35–44

[41] Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14(10): 1014–1022

[42] Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313(5795): 1960–1964

[43] Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood) 2011; 236(5): 567–579

[44] Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pagès F, Galon J. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011; 29(6): 610–618

[45] Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353(25): 2654–2666

[46] Kluger HM, Zito CR, Barr ML, Kluger HM, Zito CR,  Barr ML, Baine MK, Chiang VLS, Sznol M, Rimm DL,  Chen LP,  Jilaveanu LB. Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res 2015; 21(13): 3052–3060

[47] Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348(3): 203–213

[48] Ladanyi A, Somlai B, Gilde K, Fejos Z, Gaudi I, Timar J. T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin Cancer Res 2004; 10(2): 521–530

[49] Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, Itoh T, Ohbuchi T, Kondo S, Katoh H. Concurrent infiltration by CD8⁺ T cells and CD4⁺ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 2006; 94(2): 275–280

[50] Calabrò L, Maio M. Immune checkpoint blockade in malignant mesothelioma. Semin Oncol 2015; 42(3): 418–422

[51] Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN, Sun J, Jungbluth AA, Troncoso P, Logothetis C, Sharma P. Anti-CTLA-4 therapy results in higher CD4⁺ICOS^hi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci USA 2009; 106(8): 2729–2734

[52] Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, Logothetis C, Sharma P. CTLA-4 blockade increases IFNγ-producing CD4⁺ICOS^hi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci USA 2008; 105(39): 14987–14992

[53] Vonderheide RH, LoRusso PM, Khalil M,  Gartner EM,  Khaira D,  Soulieres D,  Dorazio P,  Trosko JA,  Rüter J,  Mariani GL,  Usari T, Domchek SM. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res 2010; 16(13): 3485–3494

[54] Ng Tang D, Shen Y, Sun J, Wen S, Wolchok JD, Yuan J, Allison JP, Sharma P. Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res 2013; 1(4): 229–234

[55] Huh JW, Lee JH, Kim HR. Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. Arch Surg 2012; 147(4): 366–372

[56] Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, Gruber SB, Gallagher RP, Zanetti R, Rosso S, Dwyer T, Venn A, Kanetsky PA, Groben PA, Hao H, Orlow I, Reiner AS, Luo L, Paine S, Ollila DW, Wilcox H, Begg CB, Berwick M. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol 2013; 31(33): 4252–4259

[57] Zeng DQ, Yu YF, Ou QY, Li XY, Zhong RZ, Xie CM, Hu QG. Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer. Oncotarget 2016; 7(12): 13765–13781

[58] Messina JL, Fenstermacher DA, Eschrich S, Qu X, Berglund AE, Lloyd MC, Schell MJ, Sondak VK, Weber JS, Mulé JJ. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep 2012; 2(1): 765

[59] Tokito T, Azuma K, Kawahara A, Ishii H, Yamada K, Matsuo N, Kinoshita T, Mizukami N, Ono H, Kage M, Hoshino T. Predictive relevance of PD-L1 expression combined with CD8⁺ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer 2016; 55: 7–14

[60] Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 2016; 17(12): e542–e551

[61] Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gómez H, Bastholt L, Chasalow SD, Berman D. 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(1): 204

[62] Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, Laghi L, Grizzi F, Asslaber M, D’Arrigo C, Vidal-Vanaclocha F, Zavadova E, Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto PA, Marincola FM, Fox BA, Pagès F. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol 2014; 232(2): 199–209

[63] Tsuchiya J, Maekawa T. Cytokinetic studies on hematopoietic cells of the bone marrow. Nihon Ketsueki Gakkai Zasshi 1973; 36(5): 641–660

[64] Galon J, Fox BA, Bifulco CB, Masucci G, Rau T, Botti G, Marincola FM, Ciliberto G, Pages F, Ascierto PA, Capone M. Immunoscore and immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med 2016; 14(1): 273

[65] Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009; 27(35): 5944–5951

[66] Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol 2017; 14(11): 655–668

[67] Ascierto PA, Capone M, Urba WJ, Bifulco CB, Botti G, Lugli A, Marincola FM, Ciliberto G, Galon J, Fox BA. The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J Transl Med 2013; 11(1): 54

[68] Paulsen EE,  Kilvaer TK,  KhanehkenariMR,  Al-SaadS,  Hald SM,  AndersenS,  RichardsenE,  NessN,  Busund LT,  Bremnes RM,  DonnemT. Assessing PDL-1 and PD-1 in non-small cell lung cancer: a novel immunoscore approach. Clin Lung Cancer 2017; 18(2): 220–333.e8

[69] Yuan J, Zhou J, Dong Z, Tandon S, Kuk D, Panageas KS, Wong P, Wu X, Naidoo J, Page DB, Wolchok JD, Hodi FS. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res 2014; 2(2): 127–132

[70] Kelderman S, Heemskerk B, van Tinteren H, van den Brom RR, Hospers GA, van den Eertwegh AJ, Kapiteijn EW, de Groot JW, Soetekouw P, Jansen RL, Fiets E, Furness AJ, Renn A, Krzystanek M, Szallasi Z, Lorigan P, Gore ME, Schumacher TN, Haanen JB, Larkin JM, Blank CU. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 2014; 63(5): 449–458

[71] Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caracò C, Curvietto M, Esposito A, Paone M, Palla M, Cavalcanti E, Sandomenico F, Petrillo A, Botti G, Fulciniti F, Palmieri G, Queirolo P, Marchetti P, Ferraresi V, Rinaldi G, Pistillo MP, Ciliberto G, Mozzillo N, Ascierto PA. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 2014; 63(7): 675–683

[72] Hannani D, Vétizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D, Desbois M, Jacquelot N, Vimond N, Chouaib S, Mateus C, Allison JP, Ribas A, Wolchok JD, Yuan J, Wong P, Postow M, Mackiewicz A, Mackiewicz J, Schadendorff D, Jaeger D, Zörnig I, Hassel J, Korman AJ, Bahjat K, Maio M, Calabro L, Teng MW, Smyth MJ, Eggermont A, Robert C, Kroemer G, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res 2015; 25(2): 208–224

[73] Delyon J, Mateus C, Lefeuvre D, Lanoy E, Zitvogel L, Chaput N, Roy S, Eggermont AM, Routier E, Robert C. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 2013; 24(6): 1697–1703

[74] Martens A, Wistuba-Hamprecht K, Geukes Foppen M,   YuanJ,  Postow MA,  Wong P,  Romano E,  Khammari A,  Dreno B,  Capone M,  Ascierto PA,  Di Giacomo AM,  Maio M,  Schilling B,  Sucker A,  Schadendorf D,  Hassel JC,  Eigentler TK,  Martus P,  Wolchok JD,  Blank C,  Pawelec G,  Garbe C,  Weide B. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 2016; 22(12): 2908–2918

[75] Schmidt H, Suciu S, Punt CJ, Gore M, Kruit W, Patel P, Lienard D, von der Maase H, Eggermont AM, Keilholz U; American Joint Committee on Cancer Stage IV Melanoma; EORTC 18951. Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer Stage IV Melanoma: results of the EORTC 18951 Biochemotherapy Trial. J Clin Oncol 2007; 25(12): 1562–1569

[76] Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L, Michielin O, Romano E, Speiser DE. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother 2014; 63(3): 247–257

[77] Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, Xu Y, Pogoriler E, Terzulli SL, Kuk D, Panageas KS, Ritter G, Sznol M, Halaban R, Jungbluth AA, Allison JP, Old LJ, Wolchok JD, Gnjatic S. Integrated NY-ESO-1 antibody and CD8⁺ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 2011; 108(40): 16723–16728

[78] Mandal R, Chan TA. Personalized oncology meets immunology: the path toward precision immunotherapy. Cancer Discov 2016; 6(7): 703–713

[79] Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264): 1084–1089

[80] Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264): 1079–1084

[81] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91–97

[82] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359(6371): 97–103

[83] Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371): 104–108

Acknowledgements

This work was supported by Shanghai Special Fund for Informatization Development (No. 201602037) and Development Initiating Grand of Shanghai Service Community.

Compliance with ethics guidelines

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, and Qijun Qian declare that they have no financial conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by a relevant institutional review board or ethics committee.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the appropriate credit is given to the original author(s) and the source, and a link is provided to the Creative Commons license, indicating if changes were made.

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2019 The Author(s) 2019. This article is published with open access at link.springer.com and journal.hep.com.cn