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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We thank Cristina Anselmi, Ornella Poffe, Francesca Hofer and Sara Sartori for outstanding technical assistance, Tiziana Cestari for cell isolation by flow sorter; Guido Kroemer, Ilaria Marigo, Ethel Cesarman, Paola Capelli, Roberto Barbazza, Loredana Ruggeri, Salvatore Paiella, Sophia Hani and Laura Pinton for reagents and helpful discussion. This work was supported by grants from Italian Association for Cancer Research (AIRC, IG grants 6599, 14103, 18603 and Special Program Molecular Clinical Oncology 5 per mille grant 12182), by grant from the Italian Ministry of Health (FINALIZZATA RF-2011-02348435 CUP:E35G1400019001), by grant from Cancer Research Institute (Clinic and Laboratory Integration Program) and by Italian Ministry of Research (MIUR, Euronanomed III call 2017, Resolve project CUP: B35D18000000006) to Vincenzo Bronte; IG AIRC 19111 to Davide Melisi; grant NIH R01 HL56067 to Bruce R. Blazar; and grant Max-Planck-Gesellshaf to Peter J. Murray. Alessandra Fiore was supported by AIRC/FIRC fellowship for abroad call 2017.
© 2018, The Author(s).