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

• DOI: 10.1038/s41467-018-07654-4
• Publication Date: 2018-11-29T16:22:08Z
• Authors: Alessandra Fiore; Stefano Ugel; Francesco De 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; Vincenzo Bronte
• Keywords: Immunosuppression Therapy; 0301 basic medicine; Science; Q; Lentivirus; CASP8 and FADD-Like Apoptosis Regulating Protein; NF-kappa B; Apoptosis; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cells; Cultured; Humans; Immunosuppression; Lentivirus; Lentivirus Infections; Monocytes; Myeloid Cells; NF-kappa B; Macrophage differentiation; Expression; Death; Chemotherapy; Inhibition; Cancer; Activation; Resistance; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cells, Cultured; Humans; Immunosuppression; Lentivirus; Lentivirus Infections; Monocytes; Myeloid Cells; NF-kappa B; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); Article; Monocytes; 3. Good health; 03 medical and health sciences; Lentivirus Infections; Humans; Myeloid Cells; MACROPHAGE DIFFERENTIATION; EXPRESSION; APOPTOSIS; CELLS; DEATH; CHEMOTHERAPY; INHIBITION; CANCER; ACTIVATION; RESISTANCE; Cells, Cultured

AbstractImmunosuppression 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.