Epigenetic regulation of myeloid regulatory cell accumulation in the tumor microenvironment

项目总结

Project Summary Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells that massively accumulate in cancer patients, including colorectal cancer patients. MDSCs not only exhibit potent immune suppressive activity to inhibit T and NK cell activation and functions to promote tumor immune evasion but also secret mediators to directly promote tumor growth. Our recent published data determined that MDSCs inhibit CTL functions through both PD-L1-dependent and PD-L1- independent mechanisms. Anti-PD-L1 immunotherapy only blocks PD-L1-dependent immune suppression. Our data thus indicate that MDSCs can inhibit CTL function even in the presence of anti-PD-1 blockade. Considering the nature of massive accumulation of MDSCs in the tumor microenvironment, the PD-L1-independent immune suppression by MDSCs may at least in part underlie colorectal cancer non-response to ICI immunotherapy. However, this is a hypothesis that remains to be tested. MDSC accumulation is due to an increase of tumor-induced myeloid cell differentiation. However, emerging data indicate that dysregulated cell death pathways also plays a key role in MDSC accumulation. Our preliminary studies identified the IL6-STAT3-DNMT epigenetic axis impairs the TNF?-RIP1 necroptosis in MDSCs to main MDSC survival and accumulation in tumor-bearing mice. Our objects in this project are to 1) elucidate the molecular mechanism underlying epigenetic repression of Tnf expression by the autocrine IL6-STAT3-DNMT axis in MDSCs in colon carcinoma in vivo, and 2) to test the hypothesis that targeting IL6 is effective to promote MDSC necroptosis to suppress MDSC accumulation to overcome colon cancer resistance to anti-PD-1 immunotherapy. Successful completion of the proposed studies will provide mechanistic insight into epigenetic regulation of MDSC accumulation in colon cancer and has a great potential to develop a targeted therapy to overcome colon cancer resistance to anti-PD-1 immunotherapy.