Kim and Kim et al. investigated the impact of conditional deletion of PD-1 (PD-1cko) in Tregs to determine its function in tumor-infiltrating (TI) Tregs. In the TC-1 lung tumor model, PD-1cko mice exhibited delayed tumor growth with reduced numbers of TITregs that were less stable, suppressive, and proliferative compared to PD-1wt Tregs. ScRNAseq analysis revealed that PD-1 signaling promoted lipid metabolism, proliferation, and suppressive pathways in TITregs, resulting in clonal expansion and suppressive capacity, while PD-1 ablation or inhibition, if it occurred prior to antigen exposure, enhanced antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the TME.
Contributed by Katherine Turner
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.