Cancers induce \u2018emergency\u2019 hematopoiesis and expansion of myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), immunosuppressive and tumor-promoting cell populations, correlated with poor prognosis and resistance to chemo-immunotherapies. Molecular characterization of these cells offers new potential therapeutic opportunities. Previously, we showed that nuclear accumulation of p50 NF-kB transcription factor in TAM regulates expression of anti-inflammatory, pro-tumoral genes. Monocytic MDSC share myeloid progenitor and immunosuppressive properties with TAM. Here, we described how p50 NF-kB
mediates the protumor functions of M-MDSC. Indeed, during cancer-related inflammation, chronic production of PGE2 induces nuclear p50 accumulation in M-MDSC, epigenetically reprogramming the response to IFN\u3b3 towards an immunosuppressive phenotype. Myeloid-specific deletion of p50 or antagonists of PGE2 receptors restore the antitumor inflammatory response to IFN\u3b3 of MMDSC.
Recently, we identified that RORC1/ROR\u3b3 drives cancer-related myelopoiesis. ROR\u3b3 is a nuclear receptor co-activated by cholesterol-related molecules (eg. oxysterols). Of note, hypercholesterolemia predisposes to cancer and induces expansion of immature monocytes. Hence, we hypothesized an interplay between cholesterol metabolism and ROR\u3b3-driven myelopoiesis. Noteworthy, while tumor bearers (mice and humans) displayed increased levels of LDL-cholesterol, diet-induced hypercholesterolemia promotes metastasis and expansion of immunosuppressive M-MDSC and TAM. ROR\u3b3 deficiency prevents hypercholesterolemia-induced
myelopoiesis disabling metastasis formation. Collectively, we identified p50 NF-kB as key driver of immunosuppressive M-MDSC in response to tumor-derived PGE2, and we underlined that ROR\u3b3 induces emergency myelopoiesis remarkably in dyslipidemic conditions. Hence, inhibitors of PGE2/p50 NF-kB and of cholesterol/ROR\u3b3 axis could be useful in the improvement of anticancer therapy
