基于肿瘤免疫微环境评估食管鳞癌新辅助放化疗疗效的研究

There is significant difference in therapeutic efficacy among patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy, which no effective methods have been found to predict accurately. Tumor immune microenvironment, as an internal characteristic of tumor, plays an important role in prognosis, but there is no study reporting the relationship between tumor immune microenvironment and therapeutic efficacy of neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma, furthermore, it is not clear about the effect of neoadjuvant chemoradiotherapy in regulating tumor immune microenvironment. Our preliminary study found that esophageal squamous cell carcinoma with large numbers of cytotoxic immune cells infiltration had a good response to neoadjuvant chemoradiotherapy, meanwhile, neoadjuvant chemoradiotherapy could enhance immune cell infiltration and PD-L1 expression. This study aims to detect the type and distribution of tumor-associated immune cells and expression of immune checkpoints of esophageal squamous cell carcinoma in pre- and post-treatment specimens, and develop an immunoscore system so as to establish a nomogram model of predicting the pathological response of esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy; analyze the changes of immune microenvironment in paired pre- and post-treatment tumor tissues, construct another nomogram model of forecasting the prognosis of esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy based on the alteration of tumor immune microenvironment; in addition, analyze the dynamic changes of immune microenvironment via the neoadjuvant chemoradiotherapy mouse model with spontaneous esophageal squamous cell carcinoma. This study is expected to elucidate the role of tumor immune microenvironment in evaluating the therapeutic efficacy of neoadjuvant chemoradiation for esophageal squamous cell carcinoma.

新辅助放化疗对食管鳞癌病人的治疗效果个体间差异明显，尚无有效手段预测新辅助放化疗的疗效，肿瘤免疫微环境作为肿瘤的内在特征，具有提示预后的重要作用，但目前尚无研究报道肿瘤免疫微环境与食管鳞癌新辅助放化疗疗效的关系，且对于新辅助放化疗在调节食管鳞癌免疫微环境中的作用也不清楚。课题组前期的研究发现富集杀伤性免疫细胞的食管鳞癌对新辅助放化疗的治疗反应较好，且新辅助放化疗能促进免疫细胞的浸润和PD-L1的表达。本课题拟检测新辅助放化疗治疗前后食管鳞癌免疫微环境中肿瘤相关免疫细胞的类型和分布，以及免疫检查点的表达情况，建立免疫评分系统来构建食管鳞癌新辅助放化疗的病理缓解预测模型；分析治疗前后配对肿瘤免疫微环境的变化，构建基于肿瘤免疫微环境变化的新辅助放化疗预后预测模型；通过小鼠自发性食管鳞癌新辅助放化疗模型，分析免疫微环境的动态变化。本研究有望阐明肿瘤免疫微环境在食管鳞癌新辅助放化疗疗效评估中的作用。

新辅助治疗食管鳞癌的最佳方案还存在争议，如何准确预测新辅助治疗的疗效和明确治疗后的肿瘤残留情况对于临床决策至关重要。按照课题设计，我们收集了新辅助治疗的食管鳞癌患者的临床病理信息、组织标本等资料，建立了新辅助治疗食管鳞癌的数据库；我们成功建立了小鼠自发性食管鳞癌模型，探索各种新辅助治疗方式对食管鳞癌的作用；在本项目的资助下，我们分析了新辅助放化疗后食管鳞癌残留肿瘤的分布特征，发现残留肿瘤可以分布于食管壁各层，肿瘤退变没有规律，淋巴结缓解率甚至低于原发灶，同时，课题组主持开展的多中心随机对照临床研究证实新辅助放化疗联合微创手术治疗食管鳞癌相比于新辅助化疗并没有显著的延长患者的生存期，具有重大临床意义。