肿瘤免疫原性对局部放射联合PD-1抗体诱导远隔效应的影响及作用机制

新近，放疗与PD-L1/PD-1通路抑制剂的联合应用在临床试验中初显成效，但不同类型肿瘤疗效差异显著，其原因未知。我们前期研究发现：局部放疗可通过T细胞应答多个环节增强机体抗肿瘤作用，但放疗在不同类型荷瘤小鼠模型中疗效差异较大，尤其对非照射野转移灶的抑制效果（即远隔效应）差异更显著，初步推测肿瘤免疫原性是影响远隔效应发生的关键因素。后续，在进一步优化放疗联合PD-1抗体治疗方案的基础上，拟用转录组测序及高通量免疫表型检测，筛查可评估肿瘤免疫原性的关键指标；并通过改变原发灶肿瘤细胞表达抗原肽种类、MHC-I表达水平及T细胞浸润数量等实验方案，深入分析肿瘤免疫原性的变化对放疗联合PD-1抗体诱导远隔效应的影响，同时探讨T细胞应答在远隔效应发生过程中的调控机制。研究结果将阐明放疗联合PD-1抗体诱导远隔效应的条件及免疫调控机制，对于临床实践中筛选适宜患者及制定有效联合方案具有重要的指导意义。

Evidence of recent clinical trials showed that the synergistic therapeutic efficacy of combination anti-PD-1 antibody with local radiotherapy was found in patients with lung squamous cell carcinoma but not in patients with breast cancer. The reason for the difference is not clear. Our previous results showed that local irradiation enhanced T cell function through several stages of adoptive immune response resulting in the inhibition of tumor growth. Nevertheless, the therapeutic efficacy of its combination with PD-1 antibody was different in several murine tumor models, especially the inhibition of the tumor growth in secondary tumor sites which was named as abscopal effect. Based on these findings, we hypothesis that the tumor immunogenicity impairs the abscopal effect induced by the combination therapy of local irradiation and anti-PD-1 antibody. There are emergence of findings demonstrated the synergistic therapeutic efficacy of radiotherapy combined with immunotherapy, but most of these data are collected from one tumor site of tumor-bearing mice. Here, using high-throughput technologies focused on immunophenotypic characterization and transcript sequencing, we will analyze the difference of immune cell profiles and immune regulatory molecules in tumor microenvironment among four murine tumor models to determine the indicated factors for the tumor immunogenicity. To further explore the impairment of the tumor immunogenicity on the abscopal effect, the abscopal tumor regression was observed in tumor models through the modification of tumor antigen peptide, the level of MHC-I molecule and infiltrating T-cell numbers in in primary tumor sites. Furthermore, we will elucidate the influence of T cell immune response on the abscopal effect following the combination therapy. All these findings not only help to reveal the inducing condition and the immune mechanisms of abscopal response in the combination treatment of local irradiation and anti-PD-1 antibody, but also provide a good rationale for treatment regime of combining radiotherapy with immune checkpoint inhibitors of PD-1 or other molecules in treatment of advanced carcinoma.