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

Myeong Joon Kim; Kyungsoo Kim; Hyo Jin Park; Gil Ran Kim; Kyeong Hee Hong; Ji Hoon Oh; Jimin Son; Dong Jin Park; Dahae Kim; Je Min Choi; Insuk Lee; Sang Jun Ha

doi:10.1038/s41590-022-01373-1

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

Myeong Joon Kim, Kyungsoo Kim, Hyo Jin Park, Gil Ran Kim, Kyeong Hee Hong, Ji Hoon Oh, Jimin Son, Dong Jin Park, Dahae Kim, Je Min Choi, Insuk Lee, Sang Jun Ha

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Pages (from-to)	148-161
Number of pages	14
Journal	Nature Immunology
Volume	24
Issue number	1
DOIs	https://doi.org/10.1038/s41590-022-01373-1
Publication status	Published - 2023 Jan

Bibliographical note

Funding Information:
This study was supported by National Research Foundation of Korea grants funded by the Korean government (2017R1A5A1014560, 2019M3A9B6065221 to S-.J.H.; 2018R1A5A2025079, 2019M3A9B6065192 to I.L.). This study was also supported by the Korean Health Technology R&D Project (HV20C0144, HN21C1410 to S-.J.H.) through the Korean Health Industry Development Institute funded by the Ministry of Health & Welfare. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41590-022-01373-1

Cite this

@article{0b33903ebbd84c168ae78dc77bd12e1e,

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

abstract = "Regulatory T (Treg) 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) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP−Cre-ERT2(+/−) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg 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 Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.",

author = "Kim, {Myeong Joon} and Kyungsoo Kim and Park, {Hyo Jin} and Kim, {Gil Ran} and Hong, {Kyeong Hee} and Oh, {Ji Hoon} and Jimin Son and Park, {Dong Jin} and Dahae Kim and Choi, {Je Min} and Insuk Lee and Ha, {Sang Jun}",

note = "Funding Information: This study was supported by National Research Foundation of Korea grants funded by the Korean government (2017R1A5A1014560, 2019M3A9B6065221 to S-.J.H.; 2018R1A5A2025079, 2019M3A9B6065192 to I.L.). This study was also supported by the Korean Health Technology R&D Project (HV20C0144, HN21C1410 to S-.J.H.) through the Korean Health Industry Development Institute funded by the Ministry of Health & Welfare. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jan,

doi = "10.1038/s41590-022-01373-1",

language = "English",

volume = "24",

pages = "148--161",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells

AU - Kim, Myeong Joon

AU - Kim, Kyungsoo

AU - Park, Hyo Jin

AU - Kim, Gil Ran

AU - Hong, Kyeong Hee

AU - Oh, Ji Hoon

AU - Son, Jimin

AU - Park, Dong Jin

AU - Kim, Dahae

AU - Choi, Je Min

AU - Lee, Insuk

AU - Ha, Sang Jun

N1 - Funding Information: This study was supported by National Research Foundation of Korea grants funded by the Korean government (2017R1A5A1014560, 2019M3A9B6065221 to S-.J.H.; 2018R1A5A2025079, 2019M3A9B6065192 to I.L.). This study was also supported by the Korean Health Technology R&D Project (HV20C0144, HN21C1410 to S-.J.H.) through the Korean Health Industry Development Institute funded by the Ministry of Health & Welfare. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023/1

Y1 - 2023/1

N2 - Regulatory T (Treg) 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) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP−Cre-ERT2(+/−) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg 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 Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.

AB - Regulatory T (Treg) 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) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP−Cre-ERT2(+/−) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg 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 Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.

UR - http://www.scopus.com/inward/record.url?scp=85145034017&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85145034017&partnerID=8YFLogxK

U2 - 10.1038/s41590-022-01373-1

DO - 10.1038/s41590-022-01373-1

M3 - Article

C2 - 36577929

AN - SCOPUS:85145034017

SN - 1529-2908

VL - 24

SP - 148

EP - 161

JO - Nature Immunology

JF - Nature Immunology

IS - 1

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this