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 - Funding Information:
The work was supported in part by Cancer Research UK programme grant A15115, Medical Research Council (MRC) Biomedical Catalyst grant MR/ L005069/1 and Bloodwise project grant 15003 to G. Franzoso, the Associazione Italiana per la Ricerca sul Cancro (AIRC) grants 1432 and 5172 and MIUR PRIN grant no. 2009EWAW4M_003 to F. Zazzeroni, MIUR FIRB grant no. RBA-P10A9H9 to E. Alesse, and the Associazione Italiana per la Ricerca sul Cancro (AIRC) grant 15585 to A. Sica. We thank N. van Rooijen for providing clodronate liposomes, I. Marigo and V. Bronte for providing the MCA-203 cell line, and J. Dyson for assistance with animal studies. We also thank V. Tybulewicz, A. Leonardi, G. Melino, and J. Behmoaras for critical reading of the manuscript. D. Verzella and B. Di Francesco were supported by the L'Aquila University PhD program in Experimental Medicine. M. Fischietti and D. Vecchiotti were supported by the L'Aquila University PhD program in Biotechnology.
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.
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U2 - 10.1158/0008-5472.CAN-17-1833
DO - 10.1158/0008-5472.CAN-17-1833
M3 - Article
C2 - 29279355
AN - SCOPUS:85042845894
SN - 0008-5472
VL - 78
SP - 1275
EP - 1292
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -
