Cgas deficiency promotes tumor growth by supporting B cell persistence and angiogenesis

Abstract

The cGAS sensor activates STING/IFN signaling, which is crucial for immune defense against pathogens and triggers inflammation in autoimmune diseases and antitumor responses. This study investigated the cGAS-mediated immune response in tumorigenesis using the MC-38 tumor model. Cgas-/- mice exhibited significantly larger tumors and lower survival rates than wild-type (WT) mice. Tumors in Cgas-/- mice showed increased fibrosis and neovascularity. WT mice mounted a more robust T-cell-mediated antitumor response, with higher levels of NK and effector T cells, while Cgas-/- mice showed an expansion of B cells, including regulatory B cells producing IL-10. B cells from tumor-bearing Cgas-/- mice survived better in the tumor- conditioned medium than those from WT mice. B cell depletion significantly reduced tumor size in WT mice but had minimal effect in Cgas-/- mice, where fibrosis and tumor vasculature persisted. Despite B cell depletion, B cells remained in the tumors of Cgas-/- mice, in contrast to WT mice, where their reduction correlated with an increase in CD8+ infiltrating cells. Expression of Tlr7 and Tlr9 remained elevated and unaffected by B cell depletion in Cgas-/- tumors, while Baff expression was higher and further increased after B cell depletion. Cgas-/- B cells promoted angiogenesis, as indicated by enhanced endothelial tube formation. In summary, cGAS deficiency fosters a tumor microenvironment that supports B cell survival, promotes a pro-tumor immune environment, and enhances angiogenesis, contributing to tumor progression.