DNA damage repair kinase DNA‐PK and cGAS synergize to induce cancer‐related inflammation in glioblastoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 27, 2022
- Source ID
- 10.15252/embj.2022111961
Entities
People
- Amel Bouzid
- Ana‐luiza Chaves Valadao
- Celine Gongora
- Claire Vanpouille-Box
- Clara Taffoni
- Clément Maghe
- Donovan Pineau
- Fabien Blanchet
- Hanane Chamma
- Isabelle K. Vila
- Jane Jardine
- Jean‐philippe Hugnot
- Johanna Marines
- Julie Gavard
- Karima Kissa
- Katarzyna Polak
- Laura Fontenille
- Maguy Del Rio
- Mara De Martino
- Mathilde Saccas
- Mi Kyung Park
- Min Sup Song
- Nadine Laguette
- Nicolas Bidère
- Soumyabrata Guha
Organizations
- Agence Nationale de la Recherche
- Agence nationale de recherches sur le SIDA
- European Research Council
- Fondation ARC pour la recherche sur le cancer
- Fondation de France
- Fondation pour la Recherche Médicale
- Institut National du Cancer
- National Center for Scientific Research
- National Institutes of Health
- National League Against Cancer
- St. Baldrick's Foundation
- United States Department of Defense
- University of Montpellier
- University of Texas at Austin
- Weill Cornell Medicine