The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T cells (Trm). In this study, we found that about 30% of tumor infiltrating lymphocytes (TILs) in TME of gastric adenocarcinoma (GAC) 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 GAC patients. 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, GAC cancer 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 GAC. 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 response 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 longevity of Trm cells and enhance antitumor immunity in GAC.

中文翻译：

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脂肪酸氧化控制胃腺癌中CD8 +组织驻留性记忆T细胞的存活。

检查点抑制剂在癌症治疗中的成功与组织驻留记忆T细胞（Trm）的浸润有关。在这项研究中，我们发现胃腺癌（GAC）TME中约30％的肿瘤浸润淋巴细胞（TIL）是CD69 + CD103 + Trm细胞。转移患者中Trm细胞的含量低，而GAC患者中Trm细胞的存在与更好的预后相关。Trm细胞表达高PD-1，TIGIT和CD39，并代表肿瘤反应性TIL。Trm细胞不是利用葡萄糖，而是依靠脂肪酸氧化来维持细胞存活。脂肪酸的缺乏导致Trm细胞死亡。在肿瘤细胞-T细胞共培养系统中，GAC癌细胞在脂质吸收方面胜过Trm细胞并诱导Trm细胞死亡。靶向PD-L1可降低GAC肿瘤细胞中的脂肪酸结合蛋白（Fabp）4和Fabp5表达。相反，PD-L1的阻滞增加了Trm细胞中Fabp4 / 5的表达，促进了Trm细胞吸收脂质，并导致Trm细胞在体内和体外的存活率更高。PD-L1阻断释放的Trm细胞，特别是在患者来源的异种移植（PDX）小鼠中。不响应PD-L1阻滞的PDX小鼠的Trm细胞少于响应者。总之，这些数据表明，Trm细胞在抗肿瘤免疫反应中代表TIL的一个子集，而代谢重编程可能是延长Trm细胞寿命并增强GAC中抗肿瘤免疫力的一种有前途的方式。促进Trm细胞吸收脂质并导致Trm细胞在体外和体内的更好存活。PD-L1阻断释放的Trm细胞，特别是在患者来源的异种移植（PDX）小鼠中。不响应PD-L1阻滞的PDX小鼠的Trm细胞少于响应者。总之，这些数据表明，Trm细胞在抗肿瘤免疫反应中代表TIL的一个子集，而代谢重编程可能是延长Trm细胞寿命并增强GAC中抗肿瘤免疫力的一种有前途的方式。促进Trm细胞吸收脂质并导致Trm细胞在体外和体内的更好存活。PD-L1阻断释放的Trm细胞，特别是在患者来源的异种移植（PDX）小鼠中。不响应PD-L1阻滞的PDX小鼠的Trm细胞少于响应者。总之，这些数据表明，Trm细胞在抗肿瘤免疫反应中代表TIL的一个子集，而代谢重编程可能是延长Trm细胞寿命并增强GAC中抗肿瘤免疫力的一种有前途的方式。