Co-inhibition of TIGIT, PD1, and Tim3 reverses dysfunction of Wilms tumor protein-1 (WT1)-specific CD8+T lymphocytes after dendritic cell vaccination in gastric cancer
机构:[1]Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China[2]Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, China诊疗科室消化内科首都医科大学附属天坛医院[3]Key Laboratory of Digestive System Tumors, Second Hospital of Lanzhou University, China[4]Department of Oncology, Beijing Anzhen Hospital Affiliated to The Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China首都医科大学附属安贞医院[5]Department of Biotherapy Center, Gansu Provincial Hospital, China[6]Department of Hemotology, Gansu Provincial Hospital, China[7]Department of Biochemistry and Molecular Biology, Hainan Medical College, China[8]Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Dendritic cell (DC) vaccines have been shown to stimulate tumor antigen-specific CD8+ T cells; however, this strategy has demonstrated variable clinical efficacy likely due to immune escape mechanisms that can induce tumor-specific CD8+ T cell dysfunction. Herein, we evaluated the functional characteristics of DC vaccine-induced CD8+ T cells with regard to immune checkpoint inhibitors in gastric cancer patients who were administered Wilms tumor protein-1 (WT1)-targeted DC vaccine. We observed the upregulation of the inhibitory molecule, TIGIT and the inhibitory T cell co-receptors PD1 and Tim3 in limiting WT1-specific CD8+ T cell growth and function in GC patients. TIGIT-expressing PD1+Tim3- CD8+ T cells were the largest subset, while TIGIT+PD1+Tim3+ was the most dysfunctional subset of WT1-specific CD8+ T cells in gastric cancer patients. Importantly, the co-inhibition of TIGIT, PD1, and Tim3 pathways enhanced the growth, proliferation, and cytokine production of WT1-specific CD8+ T cells. In conclusion, our data suggests that targeting TIGIT, PD1, and Tim3 pathways may be important in reversing immune escape in patients with advanced gastric cancer.
基金:
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81770468]; Beijing Municipal Natural Science FoundationBeijing Natural Science Foundation [7162030]; Beijing Science and Technology Plan special issue [Z14010101101]
第一作者机构:[1]Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China
共同第一作者:
通讯作者:
通讯机构:[8]Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.[*1]Department of Oncology, National Cancer Center/National Cli- nical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Pek- ing Union Medical College, No. 17 South Lane, Pan- jiayuan, Chaoyang District, Beijing 100021, China.
推荐引用方式(GB/T 7714):
Lu Xu,Liu Jingwei,Cui Peilin,et al.Co-inhibition of TIGIT, PD1, and Tim3 reverses dysfunction of Wilms tumor protein-1 (WT1)-specific CD8+T lymphocytes after dendritic cell vaccination in gastric cancer[J].AMERICAN JOURNAL OF CANCER RESEARCH.2018,8(8):1564-1575.
APA:
Lu, Xu,Liu, Jingwei,Cui, Peilin,Liu, Tao,Piao, Chunmei...&Yang, Lin.(2018).Co-inhibition of TIGIT, PD1, and Tim3 reverses dysfunction of Wilms tumor protein-1 (WT1)-specific CD8+T lymphocytes after dendritic cell vaccination in gastric cancer.AMERICAN JOURNAL OF CANCER RESEARCH,8,(8)
MLA:
Lu, Xu,et al."Co-inhibition of TIGIT, PD1, and Tim3 reverses dysfunction of Wilms tumor protein-1 (WT1)-specific CD8+T lymphocytes after dendritic cell vaccination in gastric cancer".AMERICAN JOURNAL OF CANCER RESEARCH 8..8(2018):1564-1575