The crosstalk between DNA-PK and cGAS drives tumor immunogenicity

Abstract

Cytosolic DNAs promote inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been thus suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that lack cGAS to question whether alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex drives cGAS-independent inflammatory responses but that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment, a process that impaired early tumorigenesis but correlated with poor outcome. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.

Alternative pathways driven by STING: From innate immunity to lipid metabolism

“…Recent reports indicate that STING activity in early tumors can prevent tumor initiation [179] while at later stages, chronic STING activation is essential for tumor cell survival [180] and is a poor prognostic marker for cancer patients [179,181]. To fully appreciate the role of STING in tumorigenesis, investigation of the crosstalk between STING expression and inflammatory activity and metabolic rewiring is essential.…”