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.
Author Info: (1) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Resea
Author Info: (1) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. (2) Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. (3) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. (4) Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea. Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea. (5) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. (6) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. (7) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. (8) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. (9) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. (10) Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea. Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea. Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul, Republic of Korea. Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea. (11) Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. insuklee@yonsei.ac.kr. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. insuklee@yonsei.ac.kr. (12) Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. sjha@yonsei.ac.kr. Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea. sjha@yonsei.ac.kr.
