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 - Maglie, Marcella De
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
N1 - Publisher Copyright:
©2017 American Association for Cancer Research.
PY - 2018/3/1
Y1 - 2018/3/1
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 GADD45b 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 poorclinical 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 GADD45b 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 poorclinical 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 - http://www.scopus.com/inward/record.url?scp=85042845894&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-1833
DO - 10.1158/0008-5472.CAN-17-1833
M3 - Article
SN - 0008-5472
VL - 78
SP - 1275
EP - 1292
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -