GADD45β loss ablates innate immunosuppression in cancer

Daniela Verzella; Jason Bennett; Mariafausta Fischietti; Anil Kumar 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 Forbes; Antonio Sica; Edoardo Alesse; Francesca Zazzeroni; Guido Franzoso

doi:10.1158/0008-5472.CAN-17-1833

GADD45β loss ablates innate immunosuppression in cancer

Daniela Verzella, Jason Bennett, Mariafausta Fischietti, Anil Kumar 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 Forbes, Antonio Sica, Edoardo Alesse, Francesca Zazzeroni, Guido Franzoso

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

T cell exclusion from the tumour 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 tumour-associated inflammation and T cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural 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. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.

Original language	English
Journal	Cancer Research
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-1833
Publication status	Published - 26 Dec 2017

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Journal Article

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10.1158/0008-5472.CAN-17-1833

0008-5472.CAN-17-1833.fullAccepted author manuscript, 2.57 MB

http://eprints.whiterose.ac.uk/125918/

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Verzella, D., Bennett, J., Fischietti, M., Thotakura, A. K., 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, S., Sica, A., Alesse, E., Zazzeroni, F., & Franzoso, G. (2017). GADD45β loss ablates innate immunosuppression in cancer. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-17-1833

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title = "GADD45β loss ablates innate immunosuppression in cancer",

abstract = "T cell exclusion from the tumour 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 tumour-associated inflammation and T cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural 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. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.",

keywords = "Journal Article",

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

note = "Copyright {\textcopyright}2017, American Association for Cancer Research.",

year = "2017",

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day = "26",

doi = "10.1158/0008-5472.CAN-17-1833",

language = "English",

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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, S, Sica, A, Alesse, E, Zazzeroni, F & Franzoso, G 2017, 'GADD45β loss ablates innate immunosuppression in cancer', Cancer Research. https://doi.org/10.1158/0008-5472.CAN-17-1833

TY - JOUR

T1 - GADD45β loss ablates innate immunosuppression in cancer

AU - Verzella, Daniela

AU - Bennett, Jason

AU - Fischietti, Mariafausta

AU - Thotakura, Anil Kumar

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

AU - Sica, Antonio

AU - Alesse, Edoardo

AU - Zazzeroni, Francesca

AU - Franzoso, Guido

PY - 2017/12/26

Y1 - 2017/12/26

N2 - T cell exclusion from the tumour 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 tumour-associated inflammation and T cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural 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. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.

AB - T cell exclusion from the tumour 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 tumour-associated inflammation and T cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural 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. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.

KW - Journal Article

U2 - 10.1158/0008-5472.CAN-17-1833

DO - 10.1158/0008-5472.CAN-17-1833

M3 - Article

C2 - 29279355

SN - 0008-5472

JO - Cancer Research

JF - Cancer Research

ER -

GADD45β loss ablates innate immunosuppression in cancer

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