PLA2G4A promotes right-sided colorectal cancer progression by inducing CD39+γδ Treg polarization

The γδ T cell is a promising candidate cell in tumor immunotherapy. However, γδ T cells polarize to CD39+γδ Tregs upon colorectal cancer (CRC) induction, and the underlying mechanism remains unclear. Here, we show 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. Furthermore, the quantitative mass spectrometry data show that CD39+γδ Treg polarization was related to the abnormal activation of the Phospholipase a2-IVa/Arachidonic acid (PLA2G4A/AA) metabolic pathway in RSCRC. Using an in vitro coculture system and an orthotopic murine model of CRC, we show that the overexpression of Pla2g4a in CT26 cells induced CD39+γδ Tregs, inhibiting the antitumor immune response. Finally, we found that the overall survival of the PLA2G4Ahi group was significantly shortened compared with PLA2G4Alo RSCRC, while the survival of LSCRC showed the opposite. 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 the tumor microenvironment and immunosuppression.