不同亚型微卫星高度不稳定性结直肠癌新生抗原肽的抗肿瘤免疫机制研究

Clinically, prognosis, as well as responses to immune-therapies, are different among phenotypes of high microsatellite instabilities (MSI-H) colorectal cancers, with reasons unclarified. However, our previous study indicated that those differences could attribute to the immunogenicity of different tumor-produced neo-antigens. According to that, with the self-developed AI-based tumorous neo-antigen authentication software by BGI company, we suppose to optimize high-immunogenic neo-antigens by sequencing and antigen-selection among MSI-H colorectal cancers. After optimizing, CD8+ T cells would be induced by those antigens simultaneously. Then, patients would be vaccinated with those cells and the clinical response would be evaluated to analyze the efficiency of the vaccination against different phenotypes of MSI-H colorectal cancer. Additionally, we suppose to analyze the immunological effect of CD8+ T cells induced by single neo-antigen respectively in vitro, comparing the gene expression among T cells to reveal the mechanism. The study is expected to optimize the neo-antigen combo for treatments against all phenotypes of MSI-H colorectal cancer. Furthermore, the study aims to develop targeted neo-antigen vaccine and reveal the mechanism of micro-environmental regulation of neo-antigen.

微卫星高度不稳定(MSI-H)结直肠癌预后及对免疫治疗反应差异大，其内在机制仍未揭示。前期研究提示肿瘤新生抗原的免疫原性差异可能是导致不同亚型MSI-H结直肠癌预后及对免疫治疗反应差异的原因。本研究拟在前期工作的基础上，利用合作方华大基因自主开发的基于人工智能的肿瘤新抗原鉴定软件，对不同亚型MSI-H结直肠癌患者肿瘤组织测序分析，筛选、优化不同亚型MSI-H结直肠癌的高效新生抗原肽；并应用多条新抗原共同诱导制备T细胞新抗原肽疫苗，验证其针对不同亚型MSI-H结直肠癌的临床与免疫效应。在此基础上，进一步体外分析单条新抗原肽诱导的T细胞疫苗的免疫作用，并对比不同效应T细胞的基因表达情况，研究其分子机制。本研究有望首次确立不同亚型MSI-H结直肠癌的最优的新生抗原肽组合；建立新型抗原肽MSI-H结直肠癌靶向疫苗，并阐明新抗原肽调节MSI-H结直肠癌肿瘤免疫微环境的分子机制。

微卫星高度不稳定（MSI-H）结直肠癌（CRC）预后及对免疫治疗反应差异大，其内在机制仍未揭示。前期研究提示肿瘤新生抗原的免疫原性差异可能是导致不同亚型MSI-H CRC预后及对免疫治疗反应差异的原因。本项目在前期工作基础上，通过对Lynch型和散发型MSI-H CRC肿瘤及癌旁正常样本进行全外显子和mRNA测序，分析两种不同亚型结直肠癌的高频突变基因，应用合作方的突变多肽结合能力预测软件，筛选出最高频的25个新抗原肽序列。体外合成相应的新抗原肽，并将其与不同亚型结直肠癌患者的外周血通过DC-CTL途径进行共培养，通过流式细胞术等初步验证了部分所预测的新抗原肽在体外具有免疫原性，且在不同类型结直肠癌患者中免疫原性存在差异。本研究初步筛选出具有体外免疫原性的MSI-H CRC新抗原肽，并证实这些新抗原肽在不同类型MSI-H CRC中免疫原性存在差异，这些结果为下一步建立肿瘤新抗原肽靶向的MSI-H CRC疫苗奠定了重要的研究基础，为MSI-H CRC的精准诊疗提供了新的思路和线索。