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

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 IezziMatteo Fassan, Silvio Bicciato, Bruce R. Blazar, Ugur Sahin, Peter J. Murray, Vincenzo Bronte

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number5193
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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