TY - JOUR
T1 - Induction of immunosuppressive functions and NF-κB by FLIP in monocytes
AU - Fiore, Alessandra
AU - Ugel, Stefano
AU - De Sanctis, Francesco
AU - Sandri, Sara
AU - Fracasso, Giulio
AU - Trovato, Rosalinda
AU - Sartoris, Silvia
AU - Solito, Samantha
AU - Mandruzzato, Susanna
AU - Vascotto, Fulvia
AU - Hippen, Keli L.
AU - Mondanelli, Giada
AU - Grohmann, Ursula
AU - Piro, Geny
AU - Carbone, Carmine
AU - Melisi, Davide
AU - Lawlor, Rita T.
AU - Scarpa, Aldo
AU - Lamolinara, Alessia
AU - Iezzi, Manuela
AU - Fassan, Matteo
AU - Bicciato, Silvio
AU - Blazar, Bruce R.
AU - Sahin, Ugur
AU - Murray, Peter J.
AU - Bronte, Vincenzo
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-07654-4
DO - 10.1038/s41467-018-07654-4
M3 - Article
C2 - 30518925
AN - SCOPUS:85057759747
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5193
ER -