沙门氏菌肿瘤治疗中肿瘤特异性CD8+T细胞激活的机制研究

The research on bacterial tumor therapy method is in the ascendant. The activation and functional recovery of tumor specific cytotoxicity CD8+T cells have been thought as the main reason of anti-tumor effect during the Salmonella treatment, but the molecular and mechanism involved in the activation are not yet clear. It is found that tumor-specific CD8+T cells already exist in tumor patients but are in immunosuppressive state, and Salmonella therapy can change the immunosuppressive environment in tumor. We found that the anti-tumor effect of Salmonella mutant which detect Lpp or LPS reduced significantly; while the level of interleukin -10 in serum also decreased consist with the activation of CD8+T cells. Based on the preliminary results, we propose the following hypothesis: Salmonella activated tumor-specific CD8+T cells and inhibit the growth of tumor through stimulation of IL-10.Dendritic cells is the main cell source of IL-10, LPS and Lpp as the main component of stimulus. The aim of this project is to answer the mechanism of tumor specific CD8+ T cells activation during Salmonella tumor therapy, the answer will provide more scientific evidence for improving the bacterial tumor therapy method.

细菌治疗肿瘤的研究方兴未艾，对于沙门氏菌抑制肿瘤生长的原因，多指向于沙门氏菌对肿瘤特异性细胞毒性CD8+T细胞的激活。但是,激活CD8+T细胞的分子和机理尚不清楚。我们前期结果发现，细菌肿瘤治疗组血清内的白介素-10水平明显提高；利用IL-10抗体中和血清内IL-10后，细菌抗肿瘤效果和CD8+T细胞激活水平均明显减弱。近期研究发现，肿瘤特异性CD8+T细胞上IL-10受体表达明显提高，IL-10可以直接激活肿瘤特异性CD8+T细胞，发挥抗肿瘤效果。基于前期结果和前人的研究我们提出如下科学假说：沙门氏菌通过刺激宿主分泌IL-10，激活肿瘤特异性CD8+T细胞，抑制肿瘤生长；IL-10的来源为树突状细胞;LPS和Lpp为主要刺激成分。本项目拟采用敲除株构建等方法，旨在回答沙门氏菌激活肿瘤特异性CD8+T细胞机理这一关键科学问题，为改善细菌治疗肿瘤方法提供更充分的科学依据。

目前的肿瘤免疫治疗方法在实体瘤的治疗中差强人意。本项目构建了一种沙门氏菌缺陷株，使其只在实体肿瘤中生长。细菌在多种肿瘤中均具有抗肿瘤效果。其治疗效果主要源于肿瘤环境内已有的肿瘤驻留记忆(TRM)型CD8+ T细胞的恢复、激活和增殖。我们的分析显示，CD8+ T细胞功能的再生是通过白细胞介素-10 (IL-10)/IL-10受体(IL-10R)信号通路介导的。IL-10主要是由肿瘤相关的巨噬细胞对设计细菌的肿瘤渗透反应而产生的。我们对大量的肿瘤进行表型分析，并明确了IL-10通过STAT3诱导IL-10R表达的机制。同时IL-10的表达也可以促进细菌逃避中性粒细胞吞噬。以上结果揭示了细菌肿瘤治疗的机制，提示IL-10/IL-10R表达作为免疫治疗反应的一个新的预测因子，并为通过肿瘤内免疫调节进行实体瘤提供了全新的靶点。