Epigenetic regulation of myeloid regulatory cell accumulation in the tumor microenvironment

项目摘要 髓源性抑制细胞（MDSC）是一种异质性的未成熟髓细胞群， 这些细胞在癌症患者中大量积累，包括结肠直肠癌患者。MDSCs 不仅表现出有效的免疫抑制活性以抑制T和NK细胞活化， 功能促进肿瘤免疫逃避，但也分泌介质，直接促进肿瘤 增长我们最近发表的数据确定MDSC通过两种途径抑制CTL功能， PD-L1依赖和PD-L1非依赖机制。仅抗PD-L1免疫治疗 阻断PD-L1依赖性免疫抑制。因此，我们的数据表明，MDSC可以抑制 即使在抗PD-1阻断存在下，CTL也起作用。考虑到大规模的 MDSC在肿瘤微环境中的积累，PD-L1非依赖性免疫 MDSC的抑制可能至少部分是结肠直肠癌对ICI无应答的基础 免疫疗法然而，这是一个有待检验的假设。MDSC累积为 这是由于肿瘤诱导的髓样细胞分化的增加。然而，新兴数据 表明失调的细胞死亡途径在MDSC积累中也起关键作用。我们 初步研究发现，IL 6-STAT 3-DNMT表观遗传轴损害TNF？RIP1 MDSC中的坏死性凋亡与荷瘤小鼠中的主要MDSC存活和积累相关。我们 本项目的目标是：1）阐明表观遗传的分子机制 结肠中MDSC中自分泌IL 6-STAT 3-DNMT轴对TNF表达的抑制 2）测试靶向IL 6有效促进MDSC的假设 坏死性凋亡以抑制MDSC积累，从而克服结肠癌对抗PD-1的耐药性 免疫疗法成功完成拟议的研究将提供机制的见解 研究结肠癌中MDSC积累的表观遗传调节，并具有很大的潜力， 开发靶向疗法，以克服结肠癌对抗PD-1免疫疗法的耐药性。

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.