Amino acids and RagD potentiate mTORC1 activation in CD8(+) T cells to confer antitumor immunity

Zhang, Yiwen; Hu, Hongrong; Liu, Weiwei; Yan, Shu-Mei; Li, Yuzhuang; Tan, Likai; Chen, Yingshi; Liu, Jun; Peng, Zhilin; Yuan, Yaochang; Huang, Wenjing; Yu, Fei; He, Xin; Li, Bo; Zhang, Hui

BACKGROUND: In the tumor microenvironment, tumor cells are able to suppress antitumor immunity by competing for essential nutrients, including amino acids. However, whether amino acid depletion modulates the activity of CD8(+) tumor-infiltrating lymphocytes (TILs) is unclear. METHOD: In this study, we evaluated the roles of amino acids and the Rag complex in regulating mammalian target of rapamycin complex 1 (mTORC1) signaling in CD8(+) TILs. RESULTS: We discovered that the Rag complex, particularly RagD, was crucial for CD8(+) T-cell antitumor immunity. RagD expression was positively correlated with the antitumor response of CD8(+) TILs in both murine syngeneic tumor xenografts and clinical human colon cancer samples. On RagD deficiency, CD8(+) T cells were rendered more dysfunctional, as demonstrated by attenuation of mTORC1 signaling and reductions in proliferation and cytokine secretion. Amino acids maintained RagD-mediated mTORC1 translocation to the lysosome, thereby achieving maximal mTORC1 activity in CD8(+) T cells. Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Finally, combined with antiprogrammed cell death protein 1 antibody, LEU supplementation improved T-cell immunity in MC38 tumor-bearing mice in vivo. CONCLUSION: Our results revealed that robust signaling of amino acids by RagD and downstream mTORC1 signaling were crucial for T-cell receptor-initiated antitumor immunity. The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway.