2. Academic Validation
  3. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

  • Cell Rep. 2022 Jun 21;39(12):110986. doi: 10.1016/j.celrep.2022.110986.
Jian Gu 1,  Jinren Zhou 1,  Qiuyang Chen 1,  Xiaozhang Xu 1,  Ji Gao 1,  Xiangyu Li 1,  Qing Shao 1,  Bo Zhou 1,  Haoming Zhou 1,  Song Wei 1,  Qi Wang 1,  Yuan Liang 1,  Ling Lu 2
Affiliations

Affiliations

  • 1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
  • 2 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: lvling@njmu.edu.cn.
PMID: 35732125 DOI: 10.1016/j.celrep.2022.110986
Abstract

Regulatory T (Treg) cells play a vital role in maintaining the immunosuppressive tumor microenvironment. Lactate is a crucial metabolite in Cancer and is related to tumor prognosis, metastasis, and overall survival. In this study, we focus on the effects of lactate on Treg cells. In vitro, lactate improves Treg cell stability and function, whereas lactate degradation reduces Treg cell induction, increases antitumor immunity, and decreases tumor growth in mice. Mechanistically, lactate modulates Treg cell generation through lactylation of Lys72 in MOESIN, which improves MOESIN interaction with transforming growth factor β (TGF-β) receptor I and downstream SMAD3 signaling. Cotreatment with anti-PD-1 and a Lactate Dehydrogenase Inhibitor has a stronger antitumor effect than anti-PD-1 alone. Individuals with hepatocellular carcinoma who responded to anti-PD-1 treatment have lower levels of MOESIN lactylation in Treg cells than nonresponding individuals. Thus, we identify lactate as an essential small molecule that reinforces Treg cells in the tumor microenvironment through lactylation.

Keywords

CP: Cancer; CP: Immunology; Liver cancer; MOESIN; PD-1 therapy; TGF-β; Treg cells; lactate; lactylation; tumor microenvironment.

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