低分割放疗是恶性肿瘤局部放疗的常用方式，可促进“冷肿瘤”转变成“热肿瘤”进而增强抗肿瘤免疫。但低分割放疗还可产生抑制性免疫微环境，促进治疗抵抗和肿瘤转移。我们前期结果和其他研究都证实低分割放疗可以诱导MDSC在瘤内聚集并产生免疫抑制，具体分子机制亟待深入阐明。研究MDSC在肿瘤局部和系统的动态变化，特别是阐明其向瘤内趋化及激活的机制，对选择靶向MDSC最佳时机和方法，及进一步联合治疗极为重要。我们前期证实MDSC放疗早期即在瘤内聚集和发生亚群变化，并伴有CXCR2、CXCR4以及PD-L1高表达。本项目将在前期基础上进一步研究MDSC的动态改变和亚群功能，阐明其向瘤内趋化激活的分子机制，验证CXCR2、CXCR4等不同抑制对MDSC抑制作用和对CAR-T、CTL联合治疗在瘤内聚集及杀伤活性的影响。项目实施将为深入了解放疗诱导MDSC趋化与激活，靶向干预MDSC提高免疫治疗疗效提供重要基础。

Hypofractionated radiotherapy is a common method for local radiotherapy of malignant tumors, which can promote the transformation of “cold tumors” into “hot tumors” and thus promote anti-tumor immunity. However, studies have found that hypofractionated radiotherapy can also generate immunosuppression microenvironment and promote treatment resistance and tumor metastasis. Our and other studies have confirmed that hypofractionated radiotherapy can induce myeloid derived suppressor cells (MDSCs) to accumulate in the tumor and led to immunosuppression. Specific molecular mechanisms need to be further elucidated. To study the dynamic changes of MDSCs in tumors and in vivo caused by hypofractionated radiotherapy, especially to elucidate the mechanism of MDSCs chemotaxis and activation, which is extremely important for clinicians to select the optimal timing and method for inhibiting MDSC, and to optimize the combination therapy strategy in clinical practice. We previously demonstrated that MDSCs in the early stage of radiotherapy were aggregated in tumor and subpopulation changed, accompanied by high expression of chemokine receptors CXCR2, CXCR4, and PD-L1. In this study, we will further study the dynamic changes and subgroup functions of MDSC on the basis of the previous findings to elucidate the molecular mechanisms of MDSCs chemotaxis and activation in tumor, and to verify the inhibition effect on MDSC, caused by differential inhibition of CXCR2, CXCR4, etc., and on intratumor accumulation and killing activity of cytotoxic immune cells, such as CART and OVA-CTL on this basis, to optimized the combination therapy strategy. The implementation of this project will provide an important foundation for further understanding of radiotherapy-induced MDSC chemotaxis and activation as well as specific intervention of MDSC to improve the therapeutic efficacy of malignant tumors.