γδ T cell is a promising candidate cell in tumor immunotherapy. However, γδ T cells polarized to CD39+γδ Tregs upon colorectal cancer (CRC) induction and the underlying mechanism remains unclear. Here, we discovered that the frequency of CD39+γδ Tregs, which positively correlated with poor prognosis, was significantly higher in right-sided CRC (RSCRC) than in the left-sided CRC (LSCRC). Interestingly, CD39+γδ Tregs from RSCRC showed stronger immunosuppressive phenotype and function than LSCRC. Further, the quantitative mass spectrometry data showed that CD39+γδ Tregs polarization was related to the abnormal activation of the PLA2G4A/AA metabolic pathway in RSCRC. Using an in vitro co-culture system and an orthotopic murine model of CRC, we proved that the overexpression of Pla2g4a in CT26 cells induced CD39+γδ Tregs inhibiting the anti-tumor immune response. Finally, we found that the overall survival of the PLA2G4Ahigh group was significantly shortened compared to PLA2G4Alow RSCRC, while the survival of LSCRC was on the contrary. Collectively, RSCRC with abnormal PLA2G4A expression educates γδ T cells into CD39+γδ Tregs to promote tumor progression and metastasis. Our work highlights the interaction between cancer cells and immune cells by distinguishing the primary tumor site and deepens the understanding of tumor microenvironment and immunosuppression.
Yang Zhan, Lei Zheng, Jia Liu, Dongzhi Hu, Junfeng Wang, Kai Liu, Jiansheng Guo, Ti Zhang, Dalu Kong