IMMUNE NETWORK

  • 제22권1호
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  • Pages.2.1-2.22
  • /
  • 2022
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Immune Checkpoint Inhibitors in 10 Years: Contribution of Basic Research and Clinical Application in Cancer Immunotherapy

  • Jii Bum Lee (Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine) ;
  • Hye Ryun Kim (Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine) ;
  • Sang-Jun Ha (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University)
  • 투고 : 2022.01.23
  • 심사 : 2022.02.09
  • 발행 : 2022.02.28
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⟨ 이전 논문 다음 논문 ⟩

초록

Targeting immune evasion via immune checkpoint pathways has changed the treatment paradigm in cancer. Since CTLA-4 antibody was first approved in 2011 for treatment of metastatic melanoma, eight immune checkpoint inhibitors (ICIs) centered on PD-1 pathway blockade are approved and currently administered to treat 18 different types of cancers. The first part of the review focuses on the history of CTLA-4 and PD-1 discovery and the preclinical experiments that demonstrated the possibility of anti-CTLA-4 and anti-PD-1 as anti-cancer therapeutics. The approval process of clinical trials and clinical utility of ICIs are described, specifically focusing on non-small cell lung cancer (NSCLC), in which immunotherapies are most actively applied. Additionally, this review covers the combination therapy and novel ICIs currently under investigation in NSCLC. Although ICIs are now key pivotal cancer therapy option in clinical settings, they show inconsistent therapeutic efficacy and limited responsiveness. Thus, newly proposed action mechanism to overcome the limitations of ICIs in a near future are also discussed.

키워드

과제정보

This research was funded by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science and ICT (2021R1I1A1A0105744 to J.B.L.; 2019M3A9B6065231, 2017M3A9E9072669, and 2021R1A2C2094629 to H-R.K.; 2017R1A5A1014560 and 2019M3A9B6065221 to S-J.H.). This study was also supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN21C1410).

참고문헌

  1. Coley WB. Contribution to the knowledge of sarcoma. Ann Surg 1891;14:199-220. https://doi.org/10.1097/00000658-189112000-00015
  2. Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012. CA Cancer J Clin 2012;62:309-335. https://doi.org/10.3322/caac.20132
  3. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006;24:3089-3094. https://doi.org/10.1200/JCO.2005.04.5252
  4. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-422. https://doi.org/10.1056/NEJMoa1001294
  5. Lee JB, Ha SJ, Kim HR. Clinical insights into novel immune checkpoint inhibitors. Front Pharmacol 2021;12:681320.
  6. Sengupta R, Zaidi SK. Aacr cancer progress report 2021: discovery science driving clinical breakthroughs. Clin Cancer Res 2021;27:5757-5759. https://doi.org/10.1158/1078-0432.CCR-21-3367
  7. Jeong S, Park SH. Co-stimulatory receptors in cancers and their implications for cancer immunotherapy. Immune Netw 2020;20:e3.
  8. Ha SJ, West EE, Araki K, Smith KA, Ahmed R. Manipulating both the inhibitory and stimulatory immune system towards the success of therapeutic vaccination against chronic viral infections. Immunol Rev 2008;223:317-333. https://doi.org/10.1111/j.1600-065X.2008.00638.x
  9. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987;328:267-270. https://doi.org/10.1038/328267a0
  10. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991;174:561-569. https://doi.org/10.1084/jem.174.3.561
  11. Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 1992;257:789-792. https://doi.org/10.1126/science.1323143
  12. Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992;257:792-795. https://doi.org/10.1126/science.1496399
  13. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405-413. https://doi.org/10.1016/1074-7613(94)90071-X
  14. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459-465. https://doi.org/10.1084/jem.182.2.459
  15. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995;270:985-988. https://doi.org/10.1126/science.270.5238.985
  16. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541-547. https://doi.org/10.1016/1074-7613(95)90125-6
  17. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:3887-3895. https://doi.org/10.1002/j.1460-2075.1992.tb05481.x
  18. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999;11:141-151.  https://doi.org/10.1016/S1074-7613(00)80089-8
  19. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291:319-322. https://doi.org/10.1126/science.291.5502.319
  20. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5:1365-1369. https://doi.org/10.1038/70932
  21. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001;193:839-846. https://doi.org/10.1084/jem.193.7.839
  22. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-1034. https://doi.org/10.1084/jem.192.7.1027
  23. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2:261-268. https://doi.org/10.1038/85330
  24. Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 2004;20:327-336. https://doi.org/10.1016/S1074-7613(04)00050-0
  25. Latchman YE, Liang SC, Wu Y, Chernova T, Sobel RA, Klemm M, Kuchroo VK, Freeman GJ, Sharpe AH. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci U S A 2004;101:10691-10696. https://doi.org/10.1073/pnas.0307252101
  26. Zhang Y, Chung Y, Bishop C, Daugherty B, Chute H, Holst P, Kurahara C, Lott F, Sun N, Welcher AA, et al. Regulation of T cell activation and tolerance by PDL2. Proc Natl Acad Sci U S A 2006;103:11695-11700. https://doi.org/10.1073/pnas.0601347103
  27. Liang SC, Greenwald RJ, Latchman YE, Rosas L, Satoskar A, Freeman GJ, Sharpe AH. PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur J Immunol 2006;36:58-64. https://doi.org/10.1002/eji.200535458
  28. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736. https://doi.org/10.1126/science.271.5256.1734
  29. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003;100:4712-4717. https://doi.org/10.1073/pnas.0830997100
  30. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003;100:8372-8377. https://doi.org/10.1073/pnas.1533209100
  31. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723. https://doi.org/10.1056/NEJMoa1003466
  32. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-2526. https://doi.org/10.1056/NEJMoa1104621
  33. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002;99:12293-12297. https://doi.org/10.1073/pnas.192461099
  34. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800. https://doi.org/10.1038/nm730
  35. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005;65:1089-1096. https://doi.org/10.1158/0008-5472.1089.65.3
  36. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439:682-687. https://doi.org/10.1038/nature04444
  37. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-3175. https://doi.org/10.1200/JCO.2009.26.7609
  38. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454. https://doi.org/10.1056/NEJMoa1200690
  39. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-2465. https://doi.org/10.1056/NEJMoa1200694
  40. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134-144. https://doi.org/10.1056/NEJMoa1305133
  41. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34. https://doi.org/10.1056/NEJMoa1504030
  42. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389:67-76. https://doi.org/10.1016/S0140-6736(16)32455-2
  43. Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915-1928. https://doi.org/10.1016/S0140-6736(19)32591-7
  44. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078-2092. https://doi.org/10.1056/NEJMoa1801005
  45. Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381:2020-2031. https://doi.org/10.1056/NEJMoa1910231
  46. Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016;17:1558-1568. https://doi.org/10.1016/S1470-2045(16)30366-7
  47. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220-2229. https://doi.org/10.1056/NEJMoa1809064
  48. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497-1508. https://doi.org/10.1016/S1470-2045(16)30498-3
  49. Mok TS, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-1830. https://doi.org/10.1016/S0140-6736(18)32409-7
  50. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103-1115. https://doi.org/10.1056/NEJMoa1816047
  51. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, Hermes B, Cay Senler F, Csoszi T, Fulop A, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379:2040-2051. https://doi.org/10.1056/NEJMoa1810865
  52. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD-l1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-1833. https://doi.org/10.1056/NEJMoa1606774
  53. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Updated analysis of keynote-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-l1 tumor proportion score of 50% or greater. J Clin Oncol 2019;37:537-546.
  54. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulieres D, Melichar B, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116-1127. https://doi.org/10.1056/NEJMoa1816714
  55. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:2108-2121. https://doi.org/10.1056/NEJMoa1809615
  56. Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 2021;384:2102-2114. https://doi.org/10.1056/NEJMoa2034442
  57. Eggermont AM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, et al. Adjuvant pembrolizumab versus placebo in resected stage iii melanoma. N Engl J Med 2018;378:1789-1801. https://doi.org/10.1056/NEJMoa1802357
  58. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lievre A, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 2021;384:1191-1203. https://doi.org/10.1056/NEJMoa2032125
  59. Schmid P, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-821. https://doi.org/10.1056/NEJMoa1910549
  60. Wakelee HA, Altorki NK, Zhou C, Csoszi T, Vynnychenko IO, Goloborodko O, Luft A, Akopov A, Martinez-Marti A, Kenmotsu H, et al. Impower010: Primary results of a phase iii global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage ib-iiia non-small cell lung cancer (nsclc). J Clin Oncol 2021;39 15_suppl:8500-8500. https://doi.org/10.1200/JCO.2021.39.15_suppl.8500
  61. Cetin K, Ettinger DS, Hei YJ, O'Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol 2011;3:139-148.
  62. Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:2895-2902.  https://doi.org/10.1200/JCO.2012.47.1102
  63. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98. https://doi.org/10.1056/NEJMoa011954
  64. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, D'Amico TA, et al. NCCN guidelines insights: non-small cell lung cancer, version 2.2021. J Natl Compr Canc Netw 2021;19:254-266. https://doi.org/10.6004/jnccn.2021.0013
  65. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of fda-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 2020;12:738.
  66. Steuer CE, Ramalingam SS. Advances in immunotherapy and implications for current practice in non-small-cell lung cancer. JCO Oncol Pract 2021;17:662-668. https://doi.org/10.1200/OP.21.00305
  67. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-2028. https://doi.org/10.1056/NEJMoa1501824
  68. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-135. https://doi.org/10.1056/NEJMoa1504627
  69. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-1550. https://doi.org/10.1016/S0140-6736(15)01281-7
  70. 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. https://doi.org/10.1056/NEJMoa1507643
  71. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-265. https://doi.org/10.1016/S0140-6736(16)32517-X
  72. Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, et al. Atezolizumab for first-line treatment of pd-l1-selected patients with NSCLC. N Engl J Med 2020;383:1328-1339. https://doi.org/10.1056/NEJMoa1917346
  73. Sezer A, Kilickap S, Gumus M, Bondarenko I, Ozguroglu M, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 2021;397:592-604. https://doi.org/10.1016/S0140-6736(21)00228-2
  74. Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B, Liu X, An G, Zhang W, Zhang J, et al. Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy. Cancer Sci 2016;107:1563-1571. https://doi.org/10.1111/cas.13072
  75. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol 2015;26:1813-1823. https://doi.org/10.1093/annonc/mdv209
  76. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 2015;28:690-714. https://doi.org/10.1016/j.ccell.2015.10.012
  77. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, et al.; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous nsclc. N Engl J Med 2018;378:2288-2301. https://doi.org/10.1056/NEJMoa1716948
  78. Rodriguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Domine M, Cheng SY, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol 2021;32:881-895. https://doi.org/10.1016/j.annonc.2021.04.008
  79. Paz-Ares L, Vicente D, Tafreshi A, Robinson A, Soto Parra H, Mazieres J, Hermes B, Cicin I, Medgyasszay B, Rodriguez-Cid J, et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: Protocol-specified final analysis of keynote-407. J Thorac Oncol 2020;15:1657-1669. https://doi.org/10.1016/j.jtho.2020.06.015
  80. Sheth S. Current and emerging therapies for patients with advanced non-small-cell lung cancer. Am J Health Syst Pharm 2010;67 Suppl 1:S9-S14. https://doi.org/10.2146/ajhp090457
  81. Soldera SV, Leighl NB. Update on the treatment of metastatic squamous non-small cell lung cancer in new era of personalized medicine. Front Oncol 2017;7:50.
  82. Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:198-211. https://doi.org/10.1016/S1470-2045(20)30641-0
  83. Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Janoski de Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from checkmate 9la. J Clin Oncol 2021;39 15 Suppl:9000.
  84. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, et al. Durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer. N Engl J Med 2017;377:1919-1929. https://doi.org/10.1056/NEJMoa1709937
  85. Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares LG, Vansteenkiste JF, Garassino MC, Hui R, Quantin X, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the pacific trial. J Clin Oncol 2021;39 15 Suppl:8511.
  86. Jabbour SK, Lee KH, Frost N, Breder VV, Kowalski DM, Alawin IA, Levchenko E, Reguart N, Martinez-Marti A, Houghton B, et al. Keynote-799: Phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 nsclc. J Clin Oncol 2021;39 15 Suppl:8512.
  87. Peters S, Felip E, Dafni U, Tufman A, Guckenberger M, Alvarez R, Nadal E, Becker A, Vees H, Pless M, et al. Progression-free and overall survival for concurrent nivolumab with standard concurrent chemoradiotherapy in locally advanced stage IIIa-b NSCLC: Results from the European thoracic oncology platform NICOLAS phase ii trial (European thoracic oncology platform 6-14). J Thorac Oncol 2021;16:278-288. https://doi.org/10.1016/j.jtho.2020.10.129
  88. Lin SH, Lin Y, Yao L, Kalhor N, Carter BW, Altan M, Blumenschein G, Byers LA, Fossella F, Gibbons DL, et al. Phase ii trial of concurrent atezolizumab with chemoradiation for unresectable NSCLC. J Thorac Oncol 2020;15:248-257. https://doi.org/10.1016/j.jtho.2019.10.024
  89. Bai R, Li L, Chen X, Chen N, Song W, Cui J. Neoadjuvant and adjuvant immunotherapy: opening new horizons for patients with early-stage non-small cell lung cancer. Front Oncol 2020;10:575472.
  90. Lee YJ, Lee JB, Ha SJ, Kim HR. Clinical perspectives to overcome acquired resistance to anti-programmed death-1 and anti-programmed death ligand-1 therapy in non-small cell lung cancer. Mol Cells 2021;44:363-373. https://doi.org/10.14348/molcells.2021.0044
  91. Rodriguez-Abreu D, Johnson ML, Hussein MA, Cobo M, Patel AJ, Secen NM, Lee KH, Massuti B, Hiret S, Yang JC, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol 2020;38 15 Suppl:9503.
  92. Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016;354:1160-1165. https://doi.org/10.1126/science.aaf2807
  93. Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, et al. The epigenetic landscape of T cell exhaustion. Science 2016;354:1165-1169.  https://doi.org/10.1126/science.aae0491
  94. Turner SJ, Russ BE. Can T cells be too exhausted to fight back? Science 2016;354:1104-1105. https://doi.org/10.1126/science.aal3204
  95. Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, Carter R, Awad W, Neale G, Thomas PG, et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 2017;170:142-157.e119. https://doi.org/10.1016/j.cell.2017.06.007
  96. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016;537:417-421. https://doi.org/10.1038/nature19330
  97. He R, Hou S, Liu C, Zhang A, Bai Q, Han M, Yang Y, Wei G, Shen T, Yang X, et al. Follicular CXCR5-expressing CD8(+) T cells curtail chronic viral infection. Nature 2016;537:412-428. https://doi.org/10.1038/nature19317
  98. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, et al. T cell factor 1-expressing memory-like cd8(+) T cells sustain the immune response to chronic viral infections. Immunity 2016;45:415-427. https://doi.org/10.1016/j.immuni.2016.07.021
  99. Wu T, Ji Y, Moseman EA, Xu HC, Manglani M, Kirby M, Anderson SM, Handon R, Kenyon E, Elkahloun A, et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci Immunol 2016;1:1.
  100. Leong YA, Chen Y, Ong HS, Wu D, Man K, Deleage C, Minnich M, Meckiff BJ, Wei Y, Hou Z, et al. CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles. Nat Immunol 2016;17:1187-1196. https://doi.org/10.1038/ni.3543
  101. Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 2019;20:326-336. https://doi.org/10.1038/s41590-019-0312-6
  102. Kurtulus S, Madi A, Escobar G, Klapholz M, Nyman J, Christian E, Pawlak M, Dionne D, Xia J, Rozenblatt-Rosen O, et al. Checkpoint blockade immunotherapy induces dynamic changes in PD-1(-)CD8(+) tumor-infiltrating T cells. Immunity 2019;50:181-194.e186. https://doi.org/10.1016/j.immuni.2018.11.014
  103. Chu F, Li HS, Liu X, Cao J, Ma W, Ma Y, Weng J, Zhu Z, Cheng X, Wang Z, et al. CXCR5+CD8+ T cells are a distinct functional subset with an antitumor activity. Leukemia 2019;33:2640-2653. https://doi.org/10.1038/s41375-019-0464-2
  104. Jansen CS, Prokhnevska N, Master VA, Sanda MG, Carlisle JW, Bilen MA, Cardenas M, Wilkinson S, Lake R, Sowalsky AG, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 2019;576:465-470. https://doi.org/10.1038/s41586-019-1836-5
  105. Eberhardt CS, Kissick HT, Patel MR, Cardenas MA, Prokhnevska N, Obeng RC, Nasti TH, Griffith CC, Im SJ, Wang X, et al. Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer. Nature 2021;597:279-284. https://doi.org/10.1038/s41586-021-03862-z
  106. Hudson WH, Gensheimer J, Hashimoto M, Wieland A, Valanparambil RM, Li P, Lin JX, Konieczny BT, Im SJ, Freeman GJ, et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1(+) stem-like CD8(+) T cells during chronic infection. Immunity 2019;51:1043-1058.e1044. https://doi.org/10.1016/j.immuni.2019.11.002
  107. Beltra JC, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, Casella V, Ngiow SF, Khan O, Huang YJ, et al. Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 2020;52:825-841.e828. https://doi.org/10.1016/j.immuni.2020.04.014
  108. Im SJ, Ha SJ. Re-defining t-cell exhaustion: subset, function, and regulation. Immune Netw 2020;20:e2.
  109. Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, Barber DL, Konieczny BT, Daugherty CZ, Koenig L, Yu K, et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 2017;355:1423-1427. https://doi.org/10.1126/science.aaf0683
  110. Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 2017;355:1428-1433. https://doi.org/10.1126/science.aaf1292
  111. Clouthier DL, Ohashi PS. Costimulation, a surprising connection for immunotherapy. Science 2017;355:1373-1374. https://doi.org/10.1126/science.aan1467
  112. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE, et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 2019;571:211-218. https://doi.org/10.1038/s41586-019-1325-x
  113. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 2019;571:265-269. https://doi.org/10.1038/s41586-019-1326-9
  114. Scott AC, Dundar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, Trivedi P, Menocal L, Appleby H, Camara S, et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 2019;571:270-274. https://doi.org/10.1038/s41586-019-1324-y
  115. Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, Heuston EF, Kirby M, Anderson S, Cheng J, et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat Immunol 2019;20:890-901. https://doi.org/10.1038/s41590-019-0403-4
  116. Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang YH, Lopez-Moyado IF, Georges RO, Zhang W, Onodera A, et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc Natl Acad Sci U S A 2019;116:12410-12415. https://doi.org/10.1073/pnas.1905675116
  117. Kim CG, Jang M, Kim Y, Leem G, Kim KH, Lee H, Kim TS, Choi SJ, Kim HD, Han JW, et al. VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers. Sci Immunol 2019;4:4.
  118. Kim K, Park S, Park SY, Kim G, Park SM, Cho JW, Kim DH, Park YM, Koh YW, Kim HR, et al. Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Med 2020;12:22.
  119. Wang X, He Q, Shen H, Xia A, Tian W, Yu W, Sun B. TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma. J Hepatol 2019;71:731-741. https://doi.org/10.1016/j.jhep.2019.05.015
  120. 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. https://doi.org/10.1038/s41577-019-0221-9
  121. van der Leun AM, Thommen DS, Schumacher TN. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer 2020;20:218-232. https://doi.org/10.1038/s41568-019-0235-4
  122. Kim MJ, Ha SJ. Differential role of PD-1 expressed by various immune and tumor cells in the tumor immune microenvironment: expression, function, therapeutic efficacy, and resistance to cancer immunotherapy. Front Cell Dev Biol 2021;9:767466.
  123. Zha H, Jiang Y, Wang X, Shang J, Wang N, Yu L, Zhao W, Li Z, An J, Zhang X, et al. Non-canonical PD-1 signaling in cancer and its potential implications in clinic. J Immunother Cancer 2021;9:9.
  124. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, Gupta R, Tsai JM, Sinha R, Corey D, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545:495-499. https://doi.org/10.1038/nature22396
  125. Park HJ, Kusnadi A, Lee EJ, Kim WW, Cho BC, Lee IJ, Seong J, Ha SJ. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell Immunol 2012;278:76-83. https://doi.org/10.1016/j.cellimm.2012.07.001
  126. Kim HR, Park HJ, Son J, Lee JG, Chung KY, Cho NH, Shim HS, Park S, Kim G, In Yoon H, et al. Tumor microenvironment dictates regulatory T cell phenotype: upregulated immune checkpoints reinforce suppressive function. J Immunother Cancer 2019;7:339.
  127. Son J, Cho JW, Park HJ, Moon J, Park S, Lee H, Lee J, Kim G, Park SM, Lira SA, et al. Tumor-infiltrating regulatory T-cell accumulation in the tumor microenvironment is mediated by IL33/ST2 signaling. Cancer Immunol Res 2020;8:1393-1406.  https://doi.org/10.1158/2326-6066.CIR-19-0828
  128. Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee BH, Chen L, Chang J, Chung DH, Choi I, et al. PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. J Immunol 2015;194:5801-5811. https://doi.org/10.4049/jimmunol.1401936
  129. Yoshida K, Okamoto M, Sasaki J, Kuroda C, Ishida H, Ueda K, Ideta H, Kamanaka T, Sobajima A, Takizawa T, et al. Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells. BMC Cancer 2020;20:25.
  130. Stathopoulou C, Gangaplara A, Mallett G, Flomerfelt FA, Liniany LP, Knight D, Samsel LA, Berlinguer-Palmini R, Yim JJ, Felizardo TC, et al. PD-1 inhibitory receptor downregulates asparaginyl endopeptidase and maintains foxp3 transcription factor stability in induced regulatory T cells. Immunity 2018;49:247- 263.e247. https://doi.org/10.1016/j.immuni.2018.05.006
  131. Leung CS, Yang KY, Li X, Chan VW, Ku M, Waldmann H, Hori S, Tsang JC, Lo YM, Lui KO. Single-cell transcriptomics reveal that PD-1 mediates immune tolerance by regulating proliferation of regulatory T cells. Genome Med 2018;10:71.
  132. Asano T, Meguri Y, Yoshioka T, Kishi Y, Iwamoto M, Nakamura M, Sando Y, Yagita H, Koreth J, Kim HT, et al. PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy. Blood 2017;129:2186-2197. https://doi.org/10.1182/blood-2016-09-741629
  133. 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. https://doi.org/10.1073/pnas.1822001116
  134. Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, Vitaly K, Itahashi K, Maeda Y, Matsui S, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol 2020;21:1346-1358. https://doi.org/10.1038/s41590-020-0769-3
  135. Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020;367:367.
  136. Philip M, Schietinger A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol 2021. doi: 10.1038/s41577-021-00574-3.
  137. Sautes-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 2019;19:307-325. https://doi.org/10.1038/s41568-019-0144-6
  138. Schumacher TN, Thommen DS. Tertiary lymphoid structures in cancer. Science 2022;375:eabf9419.
  139. Fairfax BP, Taylor CA, Watson RA, Nassiri I, Danielli S, Fang H, Mahe EA, Cooper R, Woodcock V, Traill Z, 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. https://doi.org/10.1038/s41591-019-0734-6
  140. Valpione S, Galvani E, Tweedy J, Mundra PA, Banyard A, Middlehurst P, Barry J, Mills S, Salih Z, Weightman J, et al. Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy. Nat Can 2020;1:210-221. https://doi.org/10.1038/s43018-019-0022-x
  141. Wu TD, Madireddi S, de Almeida PE, Banchereau R, Chen YJ, Chitre AS, Chiang EY, Iftikhar H, O'Gorman WE, Au-Yeung A, et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature 2020;579:274-278. https://doi.org/10.1038/s41586-020-2056-8
  142. Burger ML, Cruz AM, Crossland GE, Gaglia G, Ritch CC, Blatt SE, Bhutkar A, Canner D, Kienka T, Tavana SZ, et al. Antigen dominance hierarchies shape TCF1(+) progenitor CD8 T cell phenotypes in tumors. Cell 2021;184:4996-5014.e4926. https://doi.org/10.1016/j.cell.2021.08.020
  143. Connolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, Hornick NI, Fitzgerald BL, Damo M, Kasmani MY, et al. A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci Immunol 2021;6:eabg7836. 
  144. Lucca LE, Axisa PP, Lu B, Harnett B, Jessel S, Zhang L, Raddassi K, Zhang L, Olino K, Clune J, et al. Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells. J Exp Med 2021;218:218.
  145. Schenkel JM, Herbst RH, Canner D, Li A, Hillman M, Shanahan SL, Gibbons G, Smith OC, Kim JY, Westcott P, et al. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1(+) CD8(+) T cells in tumor-draining lymph nodes. Immunity 2021;54:2338-2353.e2336. https://doi.org/10.1016/j.immuni.2021.08.026