G protein-coupled receptor GPR68 inhibits lymphocyte infiltration and contributes to gender-dependent melanoma growth

Frontiers in Oncology

Oncology

Jialin Li¹  Xiaodong Song¹  Fang Xiao¹  Zhilei Huang²  Dongmei Zhong²  Wenjie Zhang²  Yunfeng Zhu²  Fu-li Xiang²  Shangmei Ye²  Jie Xu²  Mingyue Wu²  Kangdi Zhang² 

[1] Department of Critical Care Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China;Institute of Precision Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China;

关键词: melanoma;    GPR68;    gender dependence;    infiltration;    T cells;    NK cells;   

DOI  :  10.3389/fonc.2023.1202750

 received in 2023-04-09, accepted in 2023-05-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionMelanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear.MethodsWe established a syngeneic melanoma model in Gpr68-deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR.ResultsGPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45+ lymphocytes, CD8+ T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8+ T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity.DiscussionGPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients.

【 授权许可】

Unknown   
Copyright © 2023 Ye, Zhu, Zhong, Song, Li, Xiao, Huang, Zhang, Wu, Zhang, Xiang and Xu