RASSF2调控肿瘤微环境中CD103+树突状细胞浸润影响放疗疗效的机制研究

T cell immunity in the tumor microenvironment (TME) is an important determinant of radiosensitivity. Radiation is able to evoke the T cell immunity in part of the patients, but the mechanism is not well known until now. CD103+DC is the major antigen cross-presenting cells, and plays an indispensable role in the formation of T cell immunity. In our previous study, we found that after radiotherapy, the infiltrated CD103+DC is important for tumor control after radiotherapy, RASSF2 is an important determinant of radiosensitivity through editing the infiltration of CD103+DC, and miR-17-5p is negatively correlated with the expression of RASSF2, CD103+DC infiltration and tumor efficancy. So we hypothesize that in radioresistant tumor, modified by miR-17-5p, less RASSF2 is expressed and consequently less cytokine (which is important in the recruitment and activation of CD103+DC) in the TME, and finally results in radioresistance. To test this hypothesis, we will clarify: (1) the mechanism underlying the reprogramming of CD103+ DC infiltration by RASSF2; (2) the mechanism underlying the modification of RASSF2 after radiotherapy; (3) the predictive value of the above molecules. The project is expected to provide new theory of tumor radioresistance and new insights to improve radiation response through the combination of immunotherapy.

肿瘤微环境中的T细胞免疫是放疗疗效的重要决定因素。放疗能激活部分患者的T细胞免疫，但激活的具体调控机制尚不明确。CD103+DC是主要的抗原交叉提呈细胞，在T细胞免疫形成中作用重大。前期研究我们发现放疗后CD103+DC浸润程度影响放疗敏感性；肿瘤细胞中RASSF2的表达可调控CD103+DC浸润并影响放射敏感性；miR-17-5p与RASSF2表达、CD103+DC浸润、放疗疗效呈负相关。故我们假设：肿瘤细胞通过miR-17-5p抑制放疗后RASSF2表达，影响免疫细胞浸润活化相关因子的表达和分泌，导致微环境中CD103+DC浸润减少，最终产生放射抵抗。为此我们将研究：（1）RASSF2基因调节CD103+DC浸润的机制；（2）放疗调控RASSF2表达的机制；（3）相关分子作为放疗敏感性标记物的可行性。通过本研究有助于更全面地理解放射抗性产生的机制，为放疗联合免疫治疗提供新思路。

肿瘤微环境中的T细胞免疫是放疗疗效的重要决定因素。放疗能激活部分患者的T细胞免疫，但激活的具体调控机制尚不明确。CD103+树突状细胞是主要的抗原交叉提呈细胞，在T细胞免疫形成中作用重大。本研究主要就CD103+DC在肿瘤放疗敏感性中的作用及相关调控机制进行研究。研究内容主要包括：阐明CD103+DC浸润对放疗敏感性的影响，以及揭示肿瘤细胞RASSF2基因调节CD103+DC浸润的分子机制。通过研究，我们发现放射抵抗性肿瘤放疗后微环境中CD103+DC浸润受抑制，而CD103+DC 浸润影响肿瘤放疗敏感性；肿瘤组织中CD103+DC浸润与Rassf2表达相关；RASSF2的表达与XCL1的表达水平相关，而XCL1的表达与CD103+DC浸润水平和肿瘤放射敏感性呈正相关；RASSF2作为转录因子调控XCL1的转录和表达。通过本研究，我们明确了CD103+DC在肿瘤放疗敏感性中的作用，并对相关机制进行了探索，提出RASSF2和XCL1、CD103+DC作为疗效预测因子的可能性，在后期将在人标本上进行验证及转化。