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Nat Commun. 2018 Dec 5;9(1):5193. doi: 10.1038/s41467-018-07654-4.

Induction of immunosuppressive functions and NF-κB by FLIP in monocytes.

Author information

1
Department of Medicine, Section of Immunology, University of Verona, Verona, 37134, Italy.
2
Max Planck Institute of Biochemistry, Martinsried, 82152, Germany.
3
Department of Medicine, Section of Immunology, University of Verona, Verona, 37134, Italy. stefano.ugel@univr.it.
4
Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, Padova, 35124, Italy.
5
Istituto Oncologico Veneto IOV-IRCCS, Padova, 35124, Italy.
6
TRON-Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, 55131, Germany.
7
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, 55455, MN, USA.
8
Department of Experimental Medicine, University of Perugia, Perugia, 06132, Italy.
9
Department of Medicine, Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, 37134, Italy.
10
Department of Medicine, Laboratory of Oncology and Molecular Therapy, University of Verona, Verona, 37134, Italy.
11
ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, 37134, Italy.
12
Department of Pathology and Diagnostics, University of Verona, Verona, 37134, Italy.
13
Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), University G. D'Annunzio of Chieti-Pescara, Chieti, 66100, Italy.
14
Department of Medicine-DIMED, University of Padova, Padova, 35124, Italy.
15
Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, Modena, 41100, Italy.
16
University Medical Center of the Johannes Gutenberg University, Mainz, 55131, Germany.
17
Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, 55131, Germany.
18
Max Planck Institute of Biochemistry, Martinsried, 82152, Germany. murray@biochem.mpg.de.
19
Department of Medicine, Section of Immunology, University of Verona, Verona, 37134, Italy. vincenzo.bronte@univr.it.

Abstract

Immunosuppression is a hallmark of tumor progression, and treatments that inhibit or deplete monocytic myeloid-derived suppressive cells could promote anti-tumor immunity. c-FLIP is a central regulator of caspase-8-mediated apoptosis and necroptosis. Here we show that low-dose cytotoxic chemotherapy agents cause apoptosis linked to c-FLIP down-regulation selectively in monocytes. Enforced expression of c-FLIP or viral FLIP rescues monocytes from cytotoxicity and concurrently induces potent immunosuppressive activity, in T cell cultures and in vivo models of tumor progression and immunotherapy. FLIP-transduced human blood monocytes can suppress graft versus host disease. Neither expression of FLIP in granulocytes nor expression of other anti-apoptotic genes in monocytes conferred immunosuppression, suggesting that FLIP effects on immunosuppression are specific to monocytic lineage and distinct from death inhibition. Mechanistically, FLIP controls a broad transcriptional program, partially by NF-κB activation. Therefore, modulation of FLIP in monocytes offers a means to elicit or block immunosuppressive myeloid cells.

PMID:
30518925
PMCID:
PMC6281604
DOI:
10.1038/s41467-018-07654-4
[Indexed for MEDLINE]
Free PMC Article

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