Fatty Acid Oxidation Controls CD8+ Tissue-Resident Memory T-cell Survival in Gastric Adenocarcinoma
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 8 (4), 479-492
- https://doi.org/10.1158/2326-6066.cir-19-0702
Abstract
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.Keywords
Funding Information
- National Natural Science Foundation of China (30900650, 81372501, 81572260, 81871994, 81701834)
- Guangdong Natural Science Foundation (2011B031800025, S2012010008378, 2015A030313036, 2017A010101030, 2018A030310285)
- Guangzhou Science and Technology planning (2014J4100132, 2015A020214010, 2012B031800115, 2013B02180021, 2016A020215055, 201904010398, 201902020018)
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