Ripk1基因介导直肠癌放疗联合PD-1单抗免疫治疗增敏的分子机制研究

Since the irradiated tumor cell death can enhance antitumor immunity, radiotherapy (RT) combined with checkpoint blockades immunotherapy has been found as a new paradigm of cancer treatment. However, RT combined with checkpoint blockade does not achieve sustained clinical response in most patients and additional sensitizing strategies and biomarkers are therefore needed. Our previous studies showed that Ripk1 was enriched after received RT and PD-1 blockade. Also, Deletion of Ripk1 markedly decreased the response of tumors to RT combined with PD-1 blockade. It indicated that targeting Ripk1 may potentiate the effect of RT combining immunotherapy. In this project, we plan to figure out whether targeting Ripk1 could sensitize the effect of RT combining PD-1 blockade, to elucidate the mechanisms and to explore the predictive effect of RIPK1 in clinic. This project may provide new strategy to increase the sensitivity to RT combining immunotherapy in clinic and improve prognosis of cancer patients.

放疗具有免疫激活作用，与免疫治疗联合具有协同作用，但联合治疗有效率仅30-40%，寻找有效的增敏手段是亟待解决的科学难题。我们前期研究发现，放疗联合PD-1单抗免疫治疗后Ripk1基因表达明显上调，敲除Ripk1显著降低放疗联合PD-1单抗的疗效。这提示Ripk1基因可能是介导放疗联合PD-1单抗增敏的关键靶基因及有效的预测指标。本项目将通过分子、细胞、动物和临床实验深入研究Ripk1基因介导直肠癌放疗联合PD-1单抗治疗增敏的分子机制，拟解决以下问题：（1）Ripk1是否能介导放疗联合PD-1单抗免疫治疗增敏？（2）Ripk1介导放疗联合PD-1单抗治疗增敏的具体分子机制（3）RIPK1能否作为临床上放疗联合PD-1单抗疗效的预测指标？以期通过本研究进一步提高放疗联合PD-1单抗免疫治疗的疗效，进而优化直肠癌的治疗手段；同时为放疗联合免疫治疗在恶性肿瘤治疗中的应用提供具有普遍意义的证据。

免疫治疗是近几年新兴的治疗手段，大大提高了晚期患者的生存时间，但总体有效率仍然较低，寻找有效的增敏手段是亟待解决的科学难题。本项目通过一系列研究发现：① 利用TCGA等数据库检测了RIPK1 在各癌种中的表达情况：数据库分析，发现RIPK1 在各癌种中及正常组织中表达差异较大，无特定规律，这也表达RIPK1处于信号通路的上游及功能的复杂性；② 检测RIPK1 对肿瘤细胞生物学功能的影响：通过建立RIPK1 差异表达的细胞系，体内体外系列实验证实RIPK1 除促进结肠癌细胞增殖外，还能调节侵袭转移能力；③ 敲除 Ripk1 显著增强肿瘤免疫及PD-1 单抗的疗效，同时表现出远隔效应和记忆效应。这提示 Ripk1 基因可能是介导PD-1 单抗增敏的关键靶基因；④解析RIPK1 参与免疫调控的机制：Ripk1通过肿瘤细胞调节I型干扰素INF-β表达，激活DC细胞，进而引起TIL的浸润增加和活化。本研究为进一步提高放疗联合PD-1单抗免疫治疗的疗效，以及放疗联合免疫治疗在恶性肿瘤治疗中的应用提供具有普遍意义的证据。