Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells

Abstract

Regulatory T (T_reg) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) T_reg cells remains controversial. Here, we showed that conditional deletion of PD-1 in T_reg cells delayed tumor progression. In Pdcd1^fl/flFoxp3^{eGFP-Cre-ERT2(+/-)} mice, in which both PD-1-expressing and PD-1-deficient T_reg cells coexisted in the same tissue environment, conditional deletion of PD-1 in T_reg cells resulted in impairment of the proliferative and suppressive capacity of TI T_reg cells. PD-1 antibody therapy reduced the TI T_reg cell numbers, but did not directly restore the cytokine production of TI CD8⁺ T cells in TC-1 lung cancer. Single-cell analysis indicated that PD-1 signaling promoted lipid metabolism, proliferation and suppressive pathways in TI T_reg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening T_reg cell lineage stability and metabolic fitness in the tumor microenvironment.