机构:[1]Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yatsen University, Guangzhou, China.外科科室胃肠外科中山大学附属第一医院[2]Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.其他科室病理科中山大学附属第一医院[3]Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.临床科室放疗科中山大学肿瘤防治中心[4]School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China.[5]Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.医学影像科中山大学附属第一医院[6]Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.脾胃病专科外科专科广东省中医院[7]Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.临床科室胃外科中山大学肿瘤防治中心[8]Department of Gastrointestinal Surgery, Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.[9]Department of Prevention Medicine, School of Medicine, Ningbo University, Ningbo, China.[10]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yatsen University Cancer Center, Guangzhou, China.其他部门华南肿瘤学国家重点实验室中山大学肿瘤防治中心
The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT(+) was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFN gamma production, whereas CD155 overexpression inhibited T-cell metabolism and IFNg production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice. Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer. (C) 2017 AACR.
基金:
National Natural Science Foundation of China [30900650, 81372501, 81572260]; Guangdong Natural Science Foundation [2011B031800025, S2012010008378, 2015A030313036]; Guangdong/Guangzhou Science and Technology Planning Program [2014J4100132, 2015A020214010, 2013B02180021, 2016A020215055, 201704020094, 16ykjc08, 2015ykzd07, 2012B03-1800115, 2013B021800281]
语种:
外文
被引次数:
WOS:
PubmedID:
中科院(CAS)分区:
出版当年[2017]版:
大类|1 区医学
小类|1 区肿瘤学
最新[2023]版:
大类|1 区医学
小类|2 区肿瘤学
第一作者:
第一作者机构:[1]Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yatsen University, Guangzhou, China.
共同第一作者:
通讯作者:
通讯机构:[2]Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.[*1]Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
推荐引用方式(GB/T 7714):
Weiling He,Hui Zhang,Fei Han,et al.CD155T/TIGIT Signaling Regulates CD8(+) T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer[J].CANCER RESEARCH.2017,77(22):6375-6388.doi:10.1158/0008-5472.CAN-17-0381.
APA:
Weiling He,Hui Zhang,Fei Han,Xinlin Chen,Run Lin...&Zunfu Ke.(2017).CD155T/TIGIT Signaling Regulates CD8(+) T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer.CANCER RESEARCH,77,(22)
MLA:
Weiling He,et al."CD155T/TIGIT Signaling Regulates CD8(+) T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer".CANCER RESEARCH 77..22(2017):6375-6388