Myeloid-derived suppressor cell (MDSC) immunomodulation by c-FLIP

During tumor progression, cancer cells secrete many different tumor-derived factors (TDFs), like cytokines, chemokines, and metabolites, which promote the development of a flexible microenvironment inducing bot the generation of new vessels and the modification of the immune responses (Balkwill, Charles et al. 2005). Probably the most pervasive and efficient strategy of “tumor escape” relies on the tumor’s ability to create a tolerant microenvironment by modification of the normal hematopoiesis. Indeed, cancers can induce the proliferation and differentiation of myeloid precursors into myeloid cells with immunosuppressive functions. These cells, named myeloid-derive suppressor cells (MDSCs), are a heterogeneous population of myeloid cells emcompassing various stages of differentiation. MDSCs prevent the activation and functionality of T lymphocytes, limiting the success of immunotherapy strategies aimed at eradicating cancer development. In this study, we demonstrated that low dose of chemotherapeutics with different molecular targets and cytotoxic action, widely used in conventional anti-cancer therapy, were able to selectively deplete monocytic-MDSCs (M-MDSCs), restoring the T cell proliferation. We also proved that these drugs exert their action through the activation of the apoptotic death pathway and with the specific modulation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP), a well-known anti-apoptotic and drug resistance factor. In particular, recent study in mice demonstrated that the heterogeneity between the two main subsets of MDSCs, the M-MDSCs and the polymorphonuclear/granulocytic (PMN)-MDSCs, occurs from a diverse activation of the apoptotic pathways: PMN-MDSCs require the anti-apoptotic molecule MCL-1 for their development; in contrast, M-MDSC generation and survival constitutively requires the presence of c-FLIP (Haverkamp, Smith et al. 2014). Therefore, in this study we verified and demonstrated the hypothesis that c-FLIP can have also a role in driving and controlling MDSC immunosuppressive properties.