The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

Jiacheng He; Xiaolei Chai; Qiansen Zhang; Yang Wang; Yijie Wang; Xinyu Yang; Jingbo Wu; Bo Feng; Jing Sun; Weiwei Rui; Shuyin Ze; Yuanyuan Fu; Yumiao Zhao; Ying Zhang; Yao Zhang; Meizhen Liu; Chuang Liu; Meifu She; Xiangfei Hu; Xueyun Ma; Huaiyu Yang; Dawei Li; Senlin Zhao; Guichao Li; Zhen Zhang; Zhonghui Tian; Yanlin Ma; Lingyan Cao; Bo Yi; Dali Li; Ruth Nussinov; Charis Eng; Timothy A. Chan; Eytan Ruppin; J. Silvio Gutkind; Feixiong Cheng; Mingyao Liu; Weiqiang Lu

doi:10.1038/s41590-024-02068-5

The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

Jiacheng He, Xiaolei Chai, Qiansen Zhang, Yang Wang, Yijie Wang, Xinyu Yang, Jingbo Wu, Bo Feng, Jing Sun, Weiwei Rui, Shuyin Ze, Yuanyuan Fu, Yumiao Zhao, Ying Zhang, Yao Zhang, Meizhen Liu, Chuang Liu, Meifu She, Xiangfei Hu, Xueyun MaHuaiyu Yang, Dawei Li, Senlin Zhao, Guichao Li, Zhen Zhang, Zhonghui Tian, Yanlin Ma, Lingyan Cao, Bo Yi, Dali Li, Ruth Nussinov, Charis Eng, Timothy A. Chan, Eytan Ruppin, J. Silvio Gutkind, Feixiong Cheng, Mingyao Liu^*, Weiqiang Lu^*

^*Corresponding author for this work

Human Molecular Genetics Biochemistry

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

Abstract

Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2⁺ PMN-MDSCs, enhanced the activation of CD8⁺ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2⁺ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2⁺ PMN-MDSCs, boosted CD8⁺ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2⁺ PMN-MDSCs as a mechanism of immunosuppression.

Original language	English
Article number	eabi8602
Pages (from-to)	391-403
Number of pages	13
Journal	Nature Immunology
Volume	26
Issue number	3
DOIs	https://doi.org/10.1038/s41590-024-02068-5
State	Published - Mar 2025

Funding

Funders	Funder number
Innovation Platform for Academicians of Hainan Province
Hainan Province Clinical Medical Center
US government
National Cancer Institute
Zhejiang University
U.S. Department of Health and Human Services
Center for Cancer Research
Ministry of Education and Fundamental Research Funds for the Central Universities	226-2024-00062
East China Normal University	011
National Natural Science Foundation of China	82172644, 81972828, 82230002
Natural Science Research Funds of Minhang District, Shanghai	2021MHZ071
National Key Scientific Infrastructure for Translational Medicine	TMSK-2021-120
Fudan University	2020WYZT02
National Institutes of Health	HHSN261201500003I
Shanghai Key Medical Specialty Program	2024ZDXK0047

UN SDGs

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

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He, J., Chai, X., Zhang, Q., Wang, Y., Wang, Y., Yang, X., Wu, J., Feng, B., Sun, J., Rui, W., Ze, S., Fu, Y., Zhao, Y., Zhang, Y., Zhang, Y., Liu, M., Liu, C., She, M., Hu, X., ... Lu, W. (2025). The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer. Nature Immunology, 26(3), 391-403. Article eabi8602. https://doi.org/10.1038/s41590-024-02068-5

@article{6d443e0774a24cfba8eabdca67744260,

title = "The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer",

abstract = "Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.",

author = "Jiacheng He and Xiaolei Chai and Qiansen Zhang and Yang Wang and Yijie Wang and Xinyu Yang and Jingbo Wu and Bo Feng and Jing Sun and Weiwei Rui and Shuyin Ze and Yuanyuan Fu and Yumiao Zhao and Ying Zhang and Yao Zhang and Meizhen Liu and Chuang Liu and Meifu She and Xiangfei Hu and Xueyun Ma and Huaiyu Yang and Dawei Li and Senlin Zhao and Guichao Li and Zhen Zhang and Zhonghui Tian and Yanlin Ma and Lingyan Cao and Bo Yi and Dali Li and Ruth Nussinov and Charis Eng and Chan, {Timothy A.} and Eytan Ruppin and Gutkind, {J. Silvio} and Feixiong Cheng and Mingyao Liu and Weiqiang Lu",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41590-024-02068-5",

language = "אנגלית",

volume = "26",

pages = "391--403",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Research",

number = "3",

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He, J, Chai, X, Zhang, Q, Wang, Y, Wang, Y, Yang, X, Wu, J, Feng, B, Sun, J, Rui, W, Ze, S, Fu, Y, Zhao, Y, Zhang, Y, Zhang, Y, Liu, M, Liu, C, She, M, Hu, X, Ma, X, Yang, H, Li, D, Zhao, S, Li, G, Zhang, Z, Tian, Z, Ma, Y, Cao, L, Yi, B, Li, D, Nussinov, R, Eng, C, Chan, TA, Ruppin, E, Gutkind, JS, Cheng, F, Liu, M & Lu, W 2025, 'The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer', Nature Immunology, vol. 26, no. 3, eabi8602, pp. 391-403. https://doi.org/10.1038/s41590-024-02068-5

TY - JOUR

T1 - The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

AU - He, Jiacheng

AU - Chai, Xiaolei

AU - Zhang, Qiansen

AU - Wang, Yang

AU - Wang, Yijie

AU - Yang, Xinyu

AU - Wu, Jingbo

AU - Feng, Bo

AU - Sun, Jing

AU - Rui, Weiwei

AU - Ze, Shuyin

AU - Fu, Yuanyuan

AU - Zhao, Yumiao

AU - Zhang, Ying

AU - Zhang, Yao

AU - Liu, Meizhen

AU - Liu, Chuang

AU - She, Meifu

AU - Hu, Xiangfei

AU - Ma, Xueyun

AU - Yang, Huaiyu

AU - Li, Dawei

AU - Zhao, Senlin

AU - Li, Guichao

AU - Zhang, Zhen

AU - Tian, Zhonghui

AU - Ma, Yanlin

AU - Cao, Lingyan

AU - Yi, Bo

AU - Li, Dali

AU - Nussinov, Ruth

AU - Eng, Charis

AU - Chan, Timothy A.

AU - Ruppin, Eytan

AU - Gutkind, J. Silvio

AU - Cheng, Feixiong

AU - Liu, Mingyao

AU - Lu, Weiqiang

PY - 2025/3

Y1 - 2025/3

N2 - Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.

AB - Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.

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SN - 1529-2908

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JF - Nature Immunology

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M1 - eabi8602

ER -

The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

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