BATF2通过S100A9对肿瘤中PMN-MDSC的调控作用及病理意义

Myeloid deprived suppressor cell (MDSC) plays a critical role in immune suppression of malignancies. However, its intracellular molecular regulation pathway is still not clear. In our preliminary study, we found decreased expression of BATF2 in tumor induced polymorphonuclear cell MDSC (PMN-MDSC). BATF2 knock out (KO) promoted PMN-MDSC accumulation and activation in tumor bearing BATF2-KO mice, as well as tumor growth. Over expression of BATF2 reduced MDSC and S100A9 expression in MDSC, which was critical for MDSC development. Thus, we speculated that BATF2 suppressed tumor progression through regulation of PMN-MDSC differentiation via transcriptional suppression of S100A9.In the preset project, we will further confirm the presumption with following experiments. Firstly, the influence of BATF2 on PMN-MDSC in tumor will be investigated. Then, based on S100A9, the molecular mechanism in this biological process would be clearly mapped. Furthermore, the role of BATF2 in tumor growth and metastasis would be determined in tumor bearing mice modes. Finally, the association between BATF2 and PMN-MDSC as well as disease progression would be tested by study based on clinical samples. Our project will provide a novel regulatory mechanism in malignancy related PMN-MDSC, which would provide a new target for anti-cancer immunotherapy.

髓系抑制性细胞（MDSC）是肿瘤免疫耐受的重要参与者，但肿瘤中MDSC聚集及活化的调控机制尚待阐明。我们前期研究发现肿瘤来源PMN-MDSC中BATF2表达水平降低，敲除BATF2可促进PMN-MDSC聚集及活化，促进肿瘤生长；过表达BATF2可抑制MDSC产生，下降MDSC关键基因S100A9的表达。因而我们提出“BATF2通过转录抑制S100A9，从而抑制肿瘤中PMN-MDSC聚集、活化，进而抑制肿瘤生长”的科学假说。本项目拟从以下方面进行验证：研究BATF2对肿瘤中PMN-MDSC的调控作用；以S100A9为主要对象，研究BATF2调控PMN-MDSC的分子机制；探明BATF2调控PMN-MDSC对肿瘤生长及转移的影响；最后利用临床肿瘤样品分析BATF2表达与PMN-MDSC水平及病程进展之间的相关性。本项目的实施将揭示调控肿瘤中PMN-MDSC的新机制，为肿瘤免疫治疗提供新靶点。

髓系抑制性细胞（MDSC）是肿瘤免疫耐受的重要参与者，但肿瘤中MDSC聚集及活化的调控机制尚待阐明。我们前期研究发现肿瘤来源PMN-MDSC中BATF2表达水平降低，敲除BATF2可促进PMN-MDSC聚集及活化，促进肿瘤生长；过表达BATF2可抑制MDSC产生，下降MDSC关键基因S100A9的表达。因而我们提出“BATF2通过转录抑制S100A9，从而抑制肿瘤中PMN-MDSC聚集、活化，进而抑制肿瘤生长”的科学假说。.本项目在研究过程中发现，LOX-1+PMN-MDSC更加具有研究价值，并且具有独特的机制，进而进行了深入研究，主要实验结果1）肝癌患者存在LOX-1+PMN-MDSC，且与预后相关；2)内质网应激是诱导LOX-1+PMN-MDSC的关键机制；3）氧化应激是LOX-1+PMN-MDSC 的关键分子事件；4）肝癌外泌体可诱导PMN 向LOX-1+PMN-MDSC 转化；以上结果发表于Immunology(2018，第一通讯)。.进一步研究得到如下结果：肝癌外泌体通过转运ACE、诱导PMN 细胞内RAS 活化可能是其机制，进而我们提出科学假说：肝癌外泌体通过转运ACE激活PMN内RAS、诱导氧化应激，进而导致内质网应激、促进PMN 向LOX-1+PMN-MDSC 转化。以此获得国家自然科学基金面上项目：肝癌外泌体通过转运ACE激活细胞内RAS诱导LOX-1+PMN-MDSC的分子机及病理意义（81972677）。.肿瘤是一种炎症性疾病，而肝癌更是炎症直接导致的肿瘤。我们在肾衰竭这一慢性炎症状态中研究PMN-MDSC的调控机制，发现炎症状态下PMN-MDSC调控机制和肿瘤中不尽相同。发表论文于肾病1区SCI杂志Kidney Int. （2017，通讯作者）