TY - JOUR
T1 - GADD45β Loss Ablates Innate Immunosuppression in Cancer
AU - Verzella, Daniela
AU - Bennett, Jason
AU - Fischietti, Mariafausta
AU - Thotakura, Anil K.
AU - Recordati, Camilla
AU - Pasqualini, Fabio
AU - Capece, Daria
AU - Vecchiotti, Davide
AU - D'Andrea, Daniel
AU - Di Francesco, Barbara
AU - De Maglie, Marcella
AU - Begalli, Federica
AU - Tornatore, Laura
AU - Papa, Salvatore
AU - Lawrence, Toby
AU - Forbes, Stuart J.
AU - Sica, Antonio
AU - Alesse, Edoardo
AU - Zazzeroni, Francesca
AU - Franzoso, Guido
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85042845894
U2 - 10.1158/0008-5472.CAN-17-1833
DO - 10.1158/0008-5472.CAN-17-1833
M3 - Article
SN - 1538-7445
VL - 78
SP - 1275
EP - 1292
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -
