GADD45β Loss Ablates Innate Immunosuppression in Cancer

Daniela Verzella, Jason Bennett, Mariafausta Fischietti, Anil K. Thotakura, Camilla Recordati, Fabio Pasqualini, Daria Capece, Davide Vecchiotti, Daniel D'Andrea, Barbara Di Francesco, Marcella De Maglie, Federica Begalli, Laura Tornatore, Salvatore Papa, Toby Lawrence, Stuart J. Forbes, Antonio Sica, Edoardo Alesse, Francesca Zazzeroni, Guido Franzoso

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Pages (from-to)1275-1292
Number of pages18
JournalCancer Research
Volume78
Issue number5
Early online date26 Dec 2017
DOIs
Publication statusPublished - Mar 2018
Externally publishedYes

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Immunosuppression
Neoplasms
Tumor Microenvironment
T-Lymphocytes
Macrophages
Myeloid Cells
Immunotherapy
Hepatocellular Carcinoma
Carcinogenesis
Adenocarcinoma
Inflammation

Cite this

Verzella, D., Bennett, J., Fischietti, M., Thotakura, A. K., Recordati, C., Pasqualini, F., ... Franzoso, G. (2018). GADD45β Loss Ablates Innate Immunosuppression in Cancer. Cancer Research, 78(5), 1275-1292. https://doi.org/10.1158/0008-5472.CAN-17-1833

GADD45β Loss Ablates Innate Immunosuppression in Cancer. / Verzella, Daniela ; Bennett, Jason; Fischietti, Mariafausta ; Thotakura, Anil K. ; Recordati, Camilla ; Pasqualini, Fabio; Capece, Daria ; Vecchiotti, Davide ; D'Andrea, Daniel ; Di Francesco, Barbara ; De Maglie, Marcella ; Begalli, Federica; Tornatore, Laura ; Papa, Salvatore; Lawrence, Toby; Forbes, Stuart J.; Sica, Antonio; Alesse, Edoardo ; Zazzeroni, Francesca; Franzoso, Guido .

In: Cancer Research, Vol. 78, No. 5, 03.2018, p. 1275-1292.

Research output: Contribution to journalArticle

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 2018, 'GADD45β Loss Ablates Innate Immunosuppression in Cancer' Cancer Research, vol. 78, no. 5, pp. 1275-1292. https://doi.org/10.1158/0008-5472.CAN-17-1833
Verzella D, Bennett J, Fischietti M, Thotakura AK, Recordati C, Pasqualini F et al. GADD45β Loss Ablates Innate Immunosuppression in Cancer. Cancer Research. 2018 Mar;78(5):1275-1292. https://doi.org/10.1158/0008-5472.CAN-17-1833
Verzella, Daniela ; Bennett, Jason ; Fischietti, Mariafausta ; Thotakura, Anil K. ; Recordati, Camilla ; Pasqualini, Fabio ; Capece, Daria ; Vecchiotti, Davide ; D'Andrea, Daniel ; Di Francesco, Barbara ; De Maglie, Marcella ; Begalli, Federica ; Tornatore, Laura ; Papa, Salvatore ; Lawrence, Toby ; Forbes, Stuart J. ; Sica, Antonio ; Alesse, Edoardo ; Zazzeroni, Francesca ; Franzoso, Guido . / GADD45β Loss Ablates Innate Immunosuppression in Cancer. In: Cancer Research. 2018 ; Vol. 78, No. 5. pp. 1275-1292.
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