Immune Netw.  2020 Feb;20(1):e8. 10.4110/in.2020.20.e8.

Peripheral blood immune cell-based biomarkers in anti-PD-1/PD-L1 therapy

• Kim KH
• Kim CG
• Shin EC

• KMID: 2471048
• DOI: http://doi.org/10.4110/in.2020.20.e8

Abstract

Immune checkpoint blockade targeting PD-1 and PD-L1 has resulted in unprecedented clinical benefit for cancer patients. Anti-PD-1/PD-L1 therapy has become the standard treatment for diverse cancer types as monotherapy or in combination with other anti-cancer therapies, and its indications are expanding. However, many patients do not benefit from anti-PD-1/PD-L1 therapy due to primary and/or acquired resistance, which is a major obstacle to broadening the clinical applicability of anti-PD-1/PD-L1 therapy. In addition, hyperprogressive disease, an acceleration of tumor growth following anti-PD-1/PD-L1 therapy, has been proposed as a new response pattern associated with deleterious prognosis. Anti-PD-1/PD-L1 therapy can also cause a unique pattern of adverse events termed immune-related adverse events, sometimes leading to treatment discontinuation and fatal outcomes. Investigations have been carried out to predict and monitor treatment outcomes using peripheral blood as an alternative to tissue biopsy. This review summarizes recent studies utilizing peripheral blood immune cells to predict various outcomes in cancer patients treated with anti-PD-1/PD-L1 therapy.

Keyword

Blood; Biomarkers; PD-1 receptor; Programmed cell death 1 ligand 1; Prognosis; Adverse drug event

MeSH Terms

Acceleration
Antigens, CD274
Biomarkers*
Biopsy
Drug-Related Side Effects and Adverse Reactions
Fatal Outcome
Humans
Prognosis
Programmed Cell Death 1 Receptor
Antigens, CD274
Biomarkers
Programmed Cell Death 1 Receptor

Reference

References

1. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019; 37:457–495.

2. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018; 359:1350–1355.

3. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998; 188:2205–2213.

4. Gallimore A, Glithero A, Godkin A, Tissot AC, Plückthun A, Elliott T, Hengartner H, Zinkernagel R. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med. 1998; 187:1383–1393.

5. Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Araki K, Ahmed R. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med. 2018; 69:301–318.

6. Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP, et al. Defining ‘T cell exhaustion'. Nat Rev Immunol. 2019; 19:665–674.

7. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15:486–499.

8. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018; 62:29–39.

9. Cho JH. Immunotherapy for non-small-cell lung cancer: current status and future obstacles. Immune Netw. 2017; 17:378–391.

10. Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016; 44:1069–1078.

11. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017; 168:707–723.

12. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018; 360:k793.

13. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018; 4:1721–1728.

14. Champiat S, Ferrara R, Massard C, Besse B, Marabelle A, Soria JC, Ferté C. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018; 15:748–762.

15. Pitt JM, Vétizou M, Daillère R, Roberti MP, Yamazaki T, Routy B, Lepage P, Boneca IG, Chamaillard M, Kroemer G, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity. 2016; 44:1255–1269.

16. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015; 14:847–856.

17. Ilie M, Long-Mira E, Bence C, Butori C, Lassalle S, Bouhlel L, Fazzalari L, Zahaf K, Lalvée S, Washetine K, et al. Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol. 2016; 27:147–153.

18. Hofman P. PD-L1 immunohistochemistry for non-small cell lung carcinoma: which strategy should be adopted? Expert Rev Mol Diagn. 2017; 17:1097–1108.

19. Liu Y, Dong Z, Jiang T, Hou L, Wu F, Gao G, He Y, Zhao J, Li X, Zhao C, et al. Heterogeneity of PD-L1 expression among the different histological components and metastatic lymph nodes in patients with resected lung adenosquamous carcinoma. Clin Lung Cancer. 2018; 19:e421–e430.

20. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018; 362:eaar3593.

21. Lu S, Stein JE, Rimm DL, Wang DW, Bell JM, Johnson DB, Sosman JA, Schalper KA, Anders RA, Wang H, et al. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: a systematic review and meta-analysis. JAMA Oncol. 2019; 5:1195.

22. Petitprez F, de Reyniès A, Keung EZ, Chen TW, Sun CM, Calderaro J, Jeng YM, Hsiao LP, Lacroix L, Bougoüin A, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020; 577:556–560.

23. Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020; 577:561–565.

24. Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, Yizhak K, Sade-Feldman M, Blando J, Han G, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020; 577:549–555.

25. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366:883–892.

26. Lesterhuis WJ, Bosco A, Millward MJ, Small M, Nowak AK, Lake RA. Dynamic versus static biomarkers in cancer immune checkpoint blockade: unravelling complexity. Nat Rev Drug Discov. 2017; 16:264–272.

27. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515:568–571.

28. Simoni Y, Becht E, Fehlings M, Loh CY, Koo SL, Teng KW, Yeong JP, Nahar R, Zhang T, Kared H, et al. Bystander CD8⁺ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018; 557:575–579.

29. Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, Kiialainen A, Hanhart J, Schill C, Hess C, et al. A transcriptionally and functionally distinct PD-1⁺ CD8⁺ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med. 2018; 24:994–1004.

30. Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, Crystal JS, Roberts IM, et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016; 22:433–438.

31. Gros A, Tran E, Parkhurst MR, Ilyas S, Pasetto A, Groh EM, Robbins PF, Yossef R, Garcia-Garijo A, Fajardo CA, et al. Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes. J Clin Invest. 2019; 129:4992–5004.

32. Kim KH, Cho J, Ku BM, Koh J, Sun JM, Lee SH, Ahn JS, Cheon J, Min YJ, Park SH, 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.

33. Kamphorst AO, Pillai RN, Yang S, Nasti TH, Akondy RS, Wieland A, Sica GL, Yu K, Koenig L, Patel NT, 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; 114:4993–4998.

34. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017; 545:60–65.

35. Huang AC, Orlowski RJ, Xu X, Mick R, George SM, Yan PK, Manne S, Kraya AA, Wubbenhorst B, Dorfman L, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019; 25:454–461.

36. Zappasodi R, Budhu S, Hellmann MD, Postow MA, Senbabaoglu Y, Manne S, Gasmi B, Liu C, Zhong H, Li Y, et al. Non-conventional inhibitory CD4⁺ Foxp3^-PD-1 ^hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell. 2018; 33:1017–1032. e7.

37. Juliá EP, Mandó P, Rizzo MM, Cueto GR, Tsou F, Luca R, Pupareli C, Bravo AI, Astorino W, Mordoh J, et al. Peripheral changes in immune cell populations and soluble mediators after anti-PD-1 therapy in non-small cell lung cancer and renal cell carcinoma patients. Cancer Immunol Immunother. 2019; 68:1585–1596.

38. Hopkins AC, Yarchoan M, Durham JN, Yusko EC, Rytlewski JA, Robins HS, Laheru DA, Le DT, Lutz ER, Jaffee EM. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight. 2018; 3:e122092.

39. Han J, Duan J, Bai H, Wang Y, Wan R, Wang X, Chen S, Tian Y, Wang D, Fei K, 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.

40. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39:1–10.

41. Blank CU, Haanen JB, Ribas A, Schumacher TN. Cancer immunology. The “cancer immunogram”. Science. 2016; 352:658–660.

42. Zuazo M, Arasanz H, Fernández-Hinojal G, García-Granda MJ, Gato M, Bocanegra A, Martínez M, Hernández B, Teijeira L, Morilla I, et al. Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy. EMBO Mol Med. 2019; 11:e10293.

43. Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM, Dummer R, Robinson MD, Levesque MP, Becher B. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med. 2018; 24:144–153.

44. Kim HR, Park SM, Seo SU, Jung I, Yoon HI, Gabrilovich DI, Cho BC, Seong SY, Ha SJ, Youn JI. The ratio of peripheral regulatory T cells to Lox-1⁺ polymorphonuclear myeloid-derived suppressor cells predicts the early response to anti-PD-1 therapy in patients with non-small cell lung cancer. Am J Respir Crit Care Med. 2019; 199:243–246.

45. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015; 373:1627–1639.

46. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017; 376:1015–1026.

47. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016; 375:1856–1867.

48. Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018; 391:748–757.

49. Ferrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, Mazieres J, Zalcman G, Brosseau S, Le Moulec S, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. 2018; 4:1543–1552.

50. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017; 23:1920–1928.

51. Saâda-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, Even C, Fayette J, Guigay J, Loirat D, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017; 28:1605–1611.

52. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017; 23:4242–4250.

53. Kim CG, Kim KH, Pyo KH, Xin CF, Hong MH, Ahn BC, Kim Y, Choi SJ, Yoon HI, Lee JG, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol. 2019; 30:1104–1113.

54. Kim Y, Kim CH, Lee HY, Lee SH, Kim HS, Lee S, Cha H, Hong S, Kim K, Seo SW, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non-small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol. 2019; 14:1608–1618.

55. Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al. PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A. 2019; 116:9999–10008.

56. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009; 30:899–911.

57. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018; 378:158–168.

58. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles' heel of cancer immunotherapy? Nat Med. 2017; 23:540–547.

59. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010; 11:7–13.

60. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007; 8:345–350.

61. Walter U, Santamaria P. CD8+ T cells in autoimmunity. Curr Opin Immunol. 2005; 17:624–631.

62. Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001; 2:764–766.

63. Kim KH, Hur JY, Cho J, Ku BM, Koh J, Koh JY, Sun JM, Lee SH, Ahn JS, Park K, et al. Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment. OncoImmunology. 2020; 9:e1722023.

64. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008; 117:244–279.

65. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K. ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017; 28:iv119–iv142.

66. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009; 27:485–517.

67. Esfahani K, Miller WH Jr. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N Engl J Med. 2017; 376:1989–1991.

68. Johnson D, Patel AB, Uemura MI, Trinh VA, Jackson N, Zobniw CM, Tetzlaff MT, Hwu P, Curry JL, Diab A. IL17A blockade successfully treated psoriasiform dermatologic toxicity from immunotherapy. Cancer Immunol Res. 2019; 7:860–865.

69. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016; 375:1749–1755.

70. Martinez-Calle N, Rodriguez-Otero P, Villar S, Mejías L, Melero I, Prosper F, Marinello P, Paiva B, Idoate M, San-Miguel J. Anti-PD1 associated fulminant myocarditis after a single pembrolizumab dose: the role of occult pre-existing autoimmunity. Haematologica. 2018; 103:e318–e321.

71. Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, Mobley BC, Salem JE, Wang DY, Sanchez V, Wang Y, Chastain CA, et al. A case report of clonal EBV-like memory CD4⁺ T cell activation in fatal checkpoint inhibitor-induced encephalitis. Nat Med. 2019; 25:1243–1250.

72. Das R, Bar N, Ferreira M, Newman AM, Zhang L, Bailur JK, Bacchiocchi A, Kluger H, Wei W, Halaban R, et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest. 2018; 128:715–720.

73. Mammen AL, Rajan A, Pak K, Lehky T, Casciola-Rosen L, Donahue RN, Lepone LM, Zekeridou A, Pittock SJ, Hassan R, et al. Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1. Ann Rheum Dis. 2019; 78:150–152.

74. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014; 345:1623–1627.

75. Toi Y, Sugawara S, Sugisaka J, Ono H, Kawashima Y, Aiba T, Kawana S, Saito R, Aso M, Tsurumi K, et al. Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer. JAMA Oncol. 2019; 5:376–383.

76. Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, Rodriguez C, Cambridge L, Rizvi H, Wolchok JD, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017; 28:583–589.

77. Lim SY, Lee JH, Gide TN, Menzies AM, Guminski A, Carlino MS, Breen EJ, Yang JY, Ghazanfar S, Kefford RF, et al. Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Clin Cancer Res. 2019; 25:1557–1563.