Publication: GADD45β Loss Ablates Innate Immunosuppression in Cancer.

Publié dans: Cancer Res 2018 Mar; 78(5): 1275-1292

Auteurs: Verzella D, Bennett J, Fischietti M, Thotakura AK, Recordati C, Pasqualini F, Capece D, Vecchiotti D, D'Andrea D, Di Francesco B, De Maglie M, Begalli F, Tornatore L, Papa S, Lawrence T, Forbes SJ, Sica A, Alesse E, Zazzeroni F, Franzoso G

Résumé

T-cell exclusion from the tumor microenvironment (TME) is a major barrier to overcoming immune escape. Here, we identify a myeloid-intrinsic mechanism governed by the NF-κB effector molecule GADD45β that restricts tumor-associated inflammation and T-cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of proinflammatory tumor-associated macrophages (TAM) and intratumoral immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Furthermore, they suggest a therapeutic target in GADD45β for reprogramming TAM to overcome immunosuppression and T-cell exclusion from the TME.Significance: These findings define a myeloid-based immune checkpoint that restricts T-cell trafficking into tumors, with potentially important therapeutic implications to generally improve the efficacy of cancer immunotherapy. Cancer Res; 78(5); 1275-92. ©2017 AACR.

Lien vers Pubmed [PMID] – 29279355

Lien vers HAL – hal-02118047

Lien vers le DOI – 10.1158/0008-5472.CAN-17-1833