B7检查点在结直肠癌中的表达和免疫调控功能及其与PD1联合阻断的抗肿瘤效应

Colorectal cancer (CRC) is one of the most common malignant tumors, effective treatment of CRC, especially for late-stage patients, remains challenging. So far, B7 family checkpoint blockade alone and combined with other immunotherapy have become a hot topic. Our previous study found some B7 molecules, such as B7S1 and B7H3, showed abnormally high expression on tumor-infiltrating immune cells of CRC patient samples. We assume that except for PD-L1/PD1, other B7 family molecules may play important roles in tumor immune response, and their blockades combined with anti-PD1 may enhance the anti-tumor effect. Therefore, this study aims to collect 100 CRC patient surgical samples and analyze the expression pattern of some B7 family molecules in the tumor microenvironment. And we also compare the anti-tumor effect of their individual blockade in different stages of cancer patients, which could provide the basis for developing a personalized immunosuppressive therapy for different stages of cancer patients. Then, we build the inflammatory colon cancer mouse model and use selected target B7 gene knockout mice to perform in vivo and in vitro experiments, to explore their immunoregulatory function and molecular mechanism in the tumor microenvironment. Furthermore, we will compare the anti-tumor effect of the target B7 molecule blockade alone and their combined effect with anti-PD1. The current study will provide the theoretical foundation and new strategies for immune checkpoint blockade in CRC treatment.

结直肠癌是常见的恶性肿瘤之一，尤其对中晚期患者缺乏有效治疗方式。目前，B7家族免疫检查点单独及与其他疗法联合应用成为热点。本课题组前期研究发现以B7S1和B7H3为主的B7分子在结直肠癌肿瘤浸润免疫细胞上异常表达，因此我们推测除PD-L1/PD1外，其他B7分子在肠癌肿瘤免疫反应中也起到重要作用，并且其阻断剂与PD1阻断法联合应用可能增加抗肿瘤效应。因此，本项目拟收集结直肠癌患者样本100例，分析多个B7家族分子及受体在肿瘤微环境内的表达规律，并分别比较其阻断剂在不同分期患者样本上的抗肿瘤免疫效应，为不同肠癌发展阶段患者提供个性化免疫治疗提供一定依据。然后,建立小鼠炎性肠癌模型，使用筛选出的B7分子基因敲除小鼠，通过体内和体外实验，深入探讨目标B7分子在肿瘤微环境中的免疫调控分子机制，以及其单独阻断和与PD1联合阻断的抗肿瘤效应，旨在为结直肠癌的免疫靶向治疗，提供重要的理论依据和新的策略。

B7H3和B7S1是对T细胞功能起负调控作用的重要免疫检查点分子，它们过表达多种癌症中，因此我们认为它们可能是肿瘤免疫治疗的潜在靶点。在本研究中，我们发现在人结直肠癌（CRC）肿瘤微环境中，B7H3和B7S1高表达于抗原呈递细胞上，另外，CRC病人肿瘤中CD8 T细胞的功能缺陷与B7S1在抗原呈递细胞上的表达水平相关。AOM-DSS诱导的原位结直肠癌在B7S1敲除小鼠上的生长受到抑制，这种对肿瘤的抑制效应可能依赖于CD8 T和Treg细胞。这些结果说明，B7S1在结直肠癌肿瘤微环境中可能起到一定的免疫抑制性作用，为后续肿瘤免疫治疗靶点选择提供了依据。