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

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.

The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation

“…As for the potential molecular mechanisms, we verified that IMD 0354 inhibited osteoclast formation by blocking the NF-κB signaling pathway and MAPK cascade in vitro. The NF-κB and MAPK signaling pathways, which are pivotal downstream effectors of RANK-RANKL signaling, regulate osteoclastogenesis [25][26][27][28][29] . In this study, we demonstrated that IMD 0354 suppressed phosphorylation of IKKβ and IκBα, thereby blocking P65 nuclear translocation.…”

The Engagement Between MDSCs and Metastases: Partners in Crime

“…Indeed, restricted p50 translocation into nucleus limits the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers that sustain an increased release of TNFα in the tumor microenvironment (47). According to this, we demonstrated that, the enhancement of nuclear p50 translocation by c-FLIP promotes acquisition of immunosuppressive function by monocytes (42). Together, these data highlight a pivotal role of p50 on driving MDSC differentiation that needs to be better investigated in the near future.…”

“…Interestingly, we recently demonstrated that c-FLIP plays an essential role on re-programming exclusively monocytes into MDSCs without affecting cell survival since this mechanism does not affect neutrophils conversion into PMN-MDSCs. In addition, we unveiled c-FLIP as a new regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling by interaction with the p50 subunit in the nucleus therefore promoting the aberrant transcription of several immunosuppression-related genes (42). Nowadays, in the single-cell omics era, it is quite accepted that M-MDSCs and PMN-MDSCs represent the two major extremes of a continuous spectrum of myeloid cells differentiation induced by tumor and only the application of high resolution transcriptome technologies will shed light on the ontogeny of the complex and variegated world of MDSC.…”

“…The MDSC plasticity and functions are strictly guided by the activation of precise signaling pathways [extensively reviewed in (8,45)] preferentially driven by c/EBPβ (CCAAT/enhancerbinding protein) (16), STAT3 (signal transducer and activator of transcription 3) (31,46) and NF-κB (42,47) transcriptional factors. c/EBPβ is the master regulator of "emergency" myelopoiesis and its critical role on MDSC biology was proved using myeloid-restricted c/EBPβ-deficient mice engrafted with different tumor models in which the ontogeny and MDSCassociated immunosuppression were completely abrogated (16).…”

Deciphering the state of immune silence in fatal COVID-19 patients

“…Moreover, we de ned a correlation between ARG1 presence and the immunosuppressive activity of monocytes (Figure 2f), with a minor contribution of PD-L1 ( Figure S2g). Of note, CD14 + ARG1 + immune suppressive monocytes were originally de ned in patients with pancreatic cancer who also share increased levels in some in ammatory cytokines [36,37].…”