Combining TIGIT blockade with IL‐15 stimulation is a promising immunotherapy strategy for lung adenocarcinoma

作者：Baohong Luo, Yu Sun, Qinru Zhan, Yuting Luo, Yu Chen, Tongze Fu, Tiantian Yang, Lijuan Ren, Zhongpeng Xie, Xiaohua Situ, Bixia Liu, Kejing Tang, Zunfu Ke · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.1553 · 被引用次数：9 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction、Immunotherapy and Immune Responses

Abstract Background T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT) is an immune checkpoint molecule that suppresses CD8 + T‐cell function in cancer. However, the expression profile and functional significance of TIGIT in the immune microenvironment of lung adenocarcinoma (LUAD) remain elusive. Interleukin (IL)‐15 has emerged as a promising candidate for enhancing CD8 + T‐cell mediated tumour eradication. Exploring therapeutic strategies that combine IL‐15 with TIGIT blockade in LUAD is warranted. Methods We investigated the regulatory network involving coinhibitory TIGIT and CD96, as well as costimulatory CD226 in LUAD using clinical samples. The potential role of TIGIT in regulating the pathogenesis of LUAD was addressed through a murine model with transplanted tumours constructed in Tigit −/− mice. The therapeutic strategy that combines TIGIT blockade with IL‐15 stimulation was verified using a transplanted tumour murine model and a patient‐derived organoid (PDO) model. Results The frequency of TIGIT + CD8 + T cells was significantly increased in LUAD. Increased TIGIT expression indicated poorer prognosis in LUAD patients. Furthermore, the effector function of TIGIT + CD8 + tumour‐infiltrating lymphocytes (TILs) was impaired in LUAD patients and TIGIT inhibited antitumour immune response of CD8 + TILs in tumour‐bearing mice. Mechanistically, IL‐15 enhanced the effector function of CD8 + TILs but stimulated the expression of TIGIT on ...