DNA Damage Repair Kinase DNA-Pk and cGAS Synergize To Induce Cancer-Related Inflammation in Glioblastoma

Authors

Clara Taffoni
Johanna Marines
Hanane Chamma
Soumyabrata Guha
Mathilde Saccas
Amel Bouzid
Ana-Luiza Chaves Valadao
Clément Maghe
Jane Jardine
Mi Kyung Park
Katarzyna Polak
Mara De Martino
Claire Vanpouille-Box
Maguy Del Rio
Celine Gongora
Julie Gavard
Nicolas Bidère
Min Sup Song
Donovan Pineau
Jean-Philippe Hugnot
Karima Kissa
Laura Fontenille
Fabien P Blanchet
Isabelle K Vila
Nadine Laguette

Publication Date

4-3-2023

Journal

The EMBO Journal

Abstract

Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) 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 in a glioblastoma model, a process that impairs early tumorigenesis but correlates with poor outcome in glioblastoma patients. 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.

Keywords

Humans, Carcinogenesis, DNA, DNA Damage, DNA Repair, Glioblastoma, Immunity, Innate, Inflammation, Nucleotidyltransferases, Tumor Microenvironment, DNA-Activated Protein Kinase, cGAS, DNA‐PK, inflammation, tumor immunogenicity, Cancer, Immunology, Signal Transduction

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Associated Data

PMID: 36574362