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/fl)Foxp3(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.