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

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

24 Citations (Scopus)

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 language	English
Pages (from-to)	1275-1292
Number of pages	18
Journal	Cancer Research
Volume	78
Issue number	5
Early online date	26 Dec 2017
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-1833
Publication status	Published - Mar 2018
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/0008-5472.CAN-17-1833

Cite this

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. J., Sica, A., Alesse, E., Zazzeroni, F., & Franzoso, G. (2018). GADD45β Loss Ablates Innate Immunosuppression in Cancer. Cancer Research, 78(5), 1275-1292. Advance online publication. https://doi.org/10.1158/0008-5472.CAN-17-1833

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

@article{86bb6e7638cf48628cacadb1e6d31bf8,

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 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.",

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 {De Maglie}, Marcella 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",

year = "2018",

month = mar,

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

language = "English",

volume = "78",

pages = "1275--1292",

journal = "Cancer Research",

issn = "1538-7445",

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

number = "5",

}

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 - De Maglie, Marcella

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

Y1 - 2018/3

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 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.

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 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.

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

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

M3 - Article

SN - 1538-7445

VL - 78

SP - 1275

EP - 1292

JO - Cancer Research

JF - Cancer Research

IS - 5

ER -

GADD45β Loss Ablates Innate Immunosuppression in Cancer

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this