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

Qike Zhang¹  Chunmei Piao²  Jingwei Liu³  Xianghong Xu⁴  Tao Liu⁵  Xu Lu⁶  Man Xiao⁷  Peilin Cui⁸ 

[1] Department of Biochemistry and Molecular Biology, Hainan Medical College, China;Department of Biotherapy Center, Gansu Provincial Hospital, China;Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, China;Department of Hemotology, Gansu Provincial Hospital, China;Department of Oncology, Beijing Anzhen Hospital Affiliated to The Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, China;Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd, China;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;Key Laboratory of Digestive System Tumors, Second Hospital of Lanzhou University, China

关键词: TIGIT;    PD1;    Tim3;    gastric cancer;    Wilms tumor antigen;    DC vaccination;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

CC BY-NC