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

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

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

Dipartimento di Scienze del Farmaco

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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 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.

Lingua originale	Inglese
pagine (da-a)	1275-1292
Numero di pagine	18
Rivista	Cancer Research
Volume	78
Numero di pubblicazione	5
DOI	https://doi.org/10.1158/0008-5472.CAN-17-1833
Stato di pubblicazione	Pubblicato - 1 mar 2018

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10.1158/0008-5472.CAN-17-1833

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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., Maglie, M. D., Begalli, F., Tornatore, L., Papa, S., Lawrence, T., Forbes, S. J., Sica, A., Alesse, E., Zazzeroni, 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

@article{c857757adef7483a9054f4dbe1414176,

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

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 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.",

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

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

year = "2018",

month = mar,

day = "1",

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

language = "English",

volume = "78",

pages = "1275--1292",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "5",

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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, Maglie, MD, 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, n. 5, pagg. 1275-1292. 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 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

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 - 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 - 0008-5472

VL - 78

SP - 1275

EP - 1292

JO - Cancer Research

JF - Cancer Research

IS - 5

ER -

GADD45β loss ablates innate immunosuppression in cancer

Abstract

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