Fatty Acid Oxidation Controls CD8+ Tissue-Resident Memory T-cell Survival in Gastric Adenocarcinoma

作者：Run Lin, Hui Zhang, Yujie Yuan, Qiong He, Jianwen Zhou, Shuhua Li, Yu Sun, Daniel Y. Li, Hai-Bo Qiu, Wei Wang, Zhehong Zhuang, Bin Chen, Yonghui Huang, Chuwei Liu, Yingzhao Wang, Shirong Cai, Zunfu Ke, Weiling He · 发表于：Cancer Immunology Research · 年份：2020 · DOI：10.1158/2326-6066.cir-19-0702 · 被引用次数：227 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Immune Cell Function and Interaction

Abstract The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69+CD103+ Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell–T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells in vitro and in vivo. PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevi...