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

Alessandra Fiore, Stefano Ugel (), Francesco Sanctis, Sara Sandri, Giulio Fracasso, Rosalinda Trovato, Silvia Sartoris, Samantha Solito, Susanna Mandruzzato, Fulvia Vascotto, Keli L. Hippen, Giada Mondanelli, Ursula Grohmann, Geny Piro, Carmine Carbone, Davide Melisi, Rita T. Lawlor, Aldo Scarpa, Alessia Lamolinara, Manuela Iezzi, Matteo Fassan, Silvio Bicciato, Bruce R. Blazar, Ugur Sahin, Peter J. Murray () and Vincenzo Bronte ()
Additional contact information
Alessandra Fiore: University of Verona
Stefano Ugel: University of Verona
Francesco Sanctis: University of Verona
Sara Sandri: University of Verona
Giulio Fracasso: University of Verona
Rosalinda Trovato: University of Verona
Silvia Sartoris: University of Verona
Samantha Solito: University of Padova
Susanna Mandruzzato: University of Padova
Fulvia Vascotto: University Medical Center of Johannes Gutenberg University
Keli L. Hippen: University of Minnesota
Giada Mondanelli: University of Perugia
Ursula Grohmann: University of Perugia
Geny Piro: University of Verona
Carmine Carbone: University of Verona
Davide Melisi: University of Verona
Rita T. Lawlor: University and Hospital Trust of Verona
Aldo Scarpa: University and Hospital Trust of Verona
Alessia Lamolinara: University G. D’Annunzio of Chieti-Pescara
Manuela Iezzi: University G. D’Annunzio of Chieti-Pescara
Matteo Fassan: University of Padova
Silvio Bicciato: University of Modena and Reggio Emilia
Bruce R. Blazar: University of Minnesota
Ugur Sahin: University Medical Center of Johannes Gutenberg University
Peter J. Murray: Max Planck Institute of Biochemistry
Vincenzo Bronte: University of Verona

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07654-4

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