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Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F:Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71(3):209-249, 2021","DOI":"10.3322\/caac.21660"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. Paradis V:Histopathology of hepatocellular carcinoma. Recent Results Cancer Res 190:21-32, 2013","DOI":"10.1007\/978-3-642-16037-0_2"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Lee SK, Lee SW, Jang JW, Bae SH, Choi JY, Yoon SK:Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma. Int J Mol Sci 22(19), 2021","DOI":"10.3390\/ijms221910271"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4. Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B:Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459):a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 23(1):77-90, 2022","DOI":"10.1016\/S1470-2045(21)00604-5"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL, investigators K-:Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240:A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 38(3):193-202, 2020","DOI":"10.1200\/JCO.19.01307"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL, Investigators IM:Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 382(20):1894-1905, 2020","DOI":"10.1056\/NEJMoa1915745"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling THR, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I:Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040):an open-label, non-comparative, phase 1\/2 dose escalation and expansion trial. Lancet 389(10088):2492-2502, 2017","DOI":"10.1016\/S0140-6736(17)31046-2"},{"key":"8","doi-asserted-by":"publisher","unstructured":"8. Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C:Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA 315(15):1600-1609, 2016","DOI":"10.1001\/jama.2016.4059"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9. Blackburn SD, Shin H, Freeman GJ, Wherry EJ:Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A 105(39):15016-15021, 2008","DOI":"10.1073\/pnas.0801497105"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O\u2019Neil BH, Mehnert JM, Lopez J, Doi T, van Brummelen EMJ, Cristescu R, Yang P, Emancipator K, Stein K, Ayers M, Joe AK, Lunceford JK:T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers:KEYNOTE-028. J Clin Oncol 37(4):318-327, 2019","DOI":"10.1200\/JCO.2018.78.2276"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, Zhang C, Lunceford JK, Joe A, Cheng J, Webber AL, Ibrahim N, Plimack ER, Ott PA, Seiwert TY, Ribas A, McClanahan TK, Tomassini JE, Loboda A, Kaufman D:Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362(6411), 2018","DOI":"10.1126\/science.aar3593"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12. 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Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF:Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5(200):200ra116, 2013","DOI":"10.1126\/scitranslmed.3006504"},{"key":"18","doi-asserted-by":"publisher","unstructured":"18. 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 515(7528):568-571, 2014","DOI":"10.1038\/nature13954"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19. 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Bull Cancer 105(5):493-501, 2018","DOI":"10.1016\/j.bulcan.2018.01.018"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30. Harding JJ, Moreno V, Bang YJ, Hong MH, Patnaik A, Trigo J, Szpurka AM, Yamamoto N, Doi T, Fu S, Calderon B, Velez de Mendizabal N, Calvo E, Yu D, Gandhi L, Liu ZT, Galvao VR, Leow CC, de Miguel MJ:Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors:A Phase Ia\/b Study of LY3321367 with or without an Anti-PD-L1 Antibody. Clin Cancer Res 27(8):2168-2178, 2021","DOI":"10.1158\/1078-0432.CCR-20-4405"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. 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