Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer

ABSTRACT

Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8⁺T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

KEYWORDS:

• Gastric cancer
• immune resistance
• lactate
• regulatory T cells
• tumor microenvironment

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conception and design: J. Su, W.H. Guo, Y.F. Hu. Methodology, data curation, formal analysis, investigation and experiment: J. Su, X.Y. Mao, L.Z. Wang, Z.A. Chen. W.S. Wang, C.Y. Zhao. Statistical analysis, biostatistics, computational analysis: J. Su, W.H. Guo, Y.F. Hu. Writing, review, and/or revision of the manuscript: J. Su, Y.F. Hu. Administrative, technical, or material support: G.X. Li, W.H. Guo, Y.F. Hu. All authors read and approved the final manuscript.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics statement

This study was approved by the Institutional Ethics Committee of Nanfang Hospital, Southern Medical University, China. The animal experiment in this study was approved by the Animal Care and Use Committee of Southern Medical University and all procedures performed followed the guidance of the Laboratory Animal Center.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2024.2320951.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [82272062], the Funding by Science and Technology projects in Guangzhou [2023B03J0277], the Guangdong Basic and Applied Basic Research Foundation [2022A1515220014].