Hamada Tsuyoshi, Soong Thing Rinda, Masugi Yohei, Kosumi Keisuke, Nowak Jonathan A, da Silva Annacarolina, Mu Xinmeng Jasmine, Twombly Tyler S, Koh Hideo, Yang Juhong, Song Mingyang, Liu Li, Gu Mancang, Shi Yan, Nosho Katsuhiko, Morikawa Teppei, Inamura Kentaro, Shukla Sachet A, Wu Catherine J, Garraway Levi A, Zhang Xuehong, Wu Kana, Meyerhardt Jeffrey A, Chan Andrew T, Glickman Jonathan N, Rodig Scott J, Freeman Gordon J, Fuchs Charles S, Nishihara Reiko, Giannakis Marios, Ogino Shuji
Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Oncoimmunology. 2018 Mar 19;7(7):e1442999. doi: 10.1080/2162402X.2018.1442999. eCollection 2018.
Inhibitors targeting the (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor ( ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, /TIL; TIME 2, /TIL; TIME 3, /TIL; and TIME 4, /TIL). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and , , and mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, mutation, and higher amounts of neoantigens ( < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.
靶向程序性细胞死亡蛋白1（PD-1）免疫检查点通路的抑制剂彻底改变了癌症治疗策略。基于肿瘤程序性死亡配体1（PD-L1）表达和肿瘤浸润淋巴细胞（TIL）的肿瘤微环境免疫（TIME）分类已被提出用于预测免疫治疗反应。结直肠癌TIME亚型的临床、病理和分子特征仍有待确定。利用护士健康研究和卫生专业人员随访研究中的812例结肠癌和直肠癌病例，我们研究了四种TIME亚型（TIME 1，PD-L1/TIL；TIME 2，PD-L1/TIL；TIME 3，PD-L1/TIL；和TIME 4，PD-L1/TIL）与肿瘤特征和生存结果之间的关联。在生存分析中，Cox比例风险模型针对潜在混杂因素进行了调整，包括微卫星不稳定性（MSI）状态、CpG岛甲基化表型（CIMP）状态、LINE-1甲基化水平以及KRAS、NRAS和BRAF突变状态。TIME亚型1、2、3和4分别有218例（27%）、117例（14%）、103例（13%）和374例（46%）结直肠癌病例。与无TIL的亚型（TIME 1和4）相比，有TIL的亚型（TIME 2和3）与高水平MSI、高度CIMP、BRAF突变以及更高数量的新抗原相关（P<0.001）。TIME亚型与结直肠癌特异性生存或总生存无显著关联。总之，结直肠癌中有TIL的TIME亚型与高水平MSI和新抗原负荷相关，支持对癌症免疫治疗有更好的反应性。进一步研究肿瘤分子改变和肿瘤微环境中的其他因素可能为免疫预防和免疫治疗策略的制定提供信息。
