亚牛磺酸代谢调控胃癌微环境中粒细胞型髓系来源抑制性细胞形成的机制研究

粒细胞型髓系来源抑制性细胞(gMDSCs)通过干扰效应性T细胞增殖与功能，减弱肿瘤患者对免疫治疗的疗效。因此，靶向MDSCs逆转肿瘤免疫抑制微环境是改善患者预后及提高免疫治疗效果的重要策略。我们在前期研究中利用转基因小鼠胃癌模型和高通量筛选等方法，初步证实半胱氨酸亚磺酸脱羧酶（CSAD）代谢产物亚牛磺酸通过直接结合NFATc1介导了STAT3活性的调控，从而参与gMDSCs在胃癌微环境中的诱导生成。本项目拟利用胃癌临床标本和动物模型，进一步验证gMDSCs在肿瘤微环境中的浸润与胃癌恶性演进的相关性；采用突变体构建、免疫共沉淀和转基因小鼠等技术，深入阐明CSAD及其代谢物主导gMDSCs诱导形成的分子机制；并通过外泌体提取、RNA-seq、动物实验等技术探索胃癌细胞诱导gMDSCs表达CSAD的遗传/表观遗传机制，这将为改善胃癌患者免疫治疗的疗效提供新思路。

gMDSCs (granulocytic myeloid-derived suppressive cells) interfere with the proliferation and function of effector T cells to attenuate the patient’s response to immunotherapy. Therefore, how to target gMDSCs represents a major research focus to enhance the prognosis of cancer patients and restore the efficiency of immunotherapy. In our preliminary studies, we observed that hypotaurine, the metabolic product of cysteine sulfinic acid decarboxylase (CSAD), binds to NFATc1 and activates STAT3 by facilitating NFATc1 disassociation with STAT3. Thereby, hypotaurine is critical for gMDSCs formation in tumor microenvironment of gastric cancer. Here, we aim to uncover the association between gMDSCs formation and progression, as well as prognosis of gastric cancer both in in vivo and in vitro. Utilizing mutant vectors, GST pull down and transgenic mice, we attempt to clarify hypotaurine-mediated mechanism involved in gMDSCs formation. By performing exosomes isolation, RNA-sequencing and tumor transplantation, we try to elucidate the genetic/epigenetic mechanism underlying CSAD expression induced by cross-talk between gMDSCs and gastric cancer cells. Thus, further support of this program would provide a promising perspective to improve the therapeutic effect of immunotherapy against gastric cancer.