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.

Induction of immunosuppressive functions and NF-κB by FLIP in monocytes / Fiore, Alessandra; Ugel, Stefano; De Sanctis, Francesco; Sandri, Sara; Fracasso, Giulio; Trovato, Rosalinda; Sartoris, Silvia; Solito, Samantha; Mandruzzato, Susanna; Vascotto, Fulvia; Hippen, Keli L.; Mondanelli, Giada; Grohmann, Ursula; Piro, Geny; Carbone, Carmine; Melisi, Davide; Lawlor, Rita T.; Scarpa, Aldo; Lamolinara, Alessia; Iezzi, Manuela; Fassan, Matteo; Bicciato, Silvio; Blazar, Bruce R.; Sahin, Ugur; Murray, Peter J.; Bronte, Vincenzo. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 9:1(2018), pp. 5193-5206.

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