PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis

Abstract

The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8⁺ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8⁺ T cells than in circulating CD8⁺ T cells. Intratumoral CD8⁺ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1^-/- CD8⁺ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8⁺ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8⁺ T cell antitumor function but did not rescue dysfunction of Plpp1^-/- CD8⁺ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8⁺ T cells, with therapeutic implications for immunotherapy.

Keywords: CD8(+) T cell; PD-1 signaling; PLPP1; anti-PD-1 therapy; antitumor immunity; ferroptosis; lipid peroxidation; phospholipid metabolism; tumor microenvironment; unsaturated fatty acid.