调节性T淋巴细胞在肿瘤免疫治疗超进展现象中的作用及机制研究

Significant breakthrough have been made in cancer immunotherapy lately. However, about 10% of patients suffer from hyperprogressive disease(HPD) after immunotherapy and the mechanism remains unclear. Regulatory T cells (Treg) is the most vital immunoregulatory cell and its role in HPD after immunotherapy remains unknown. Our preliminary experiments found that (1)Treg cell resident in tumor tissue express high level PD-1, (2)Proportion of Treg cells in HPD patients before treatment was higher than that in non-HPD patients,(3)the proportion of Treg cells in tumor tissues of HPD patients increased after PD-1 therapy. Based on these facts, we postulate that anti-PD-1 antibody promotes the proliferation of Treg cells and enhances its inhibitory function, which is the possible reason triggering HPD after immunotherapy. This project aims measuring the effect of anti-PD-1 antibody on the proportion and function of Treg cells both clinically and experimentally and screening signal pathways involved. This project will not only unreveal the role of Treg cells in the HPD induced by anti-PD-1 antibody and its potential mechanism, but also provide new ideas for the screening of the dominant population of anti-cancer immunotherapy and promote the development of precise immunotherapy.

肿瘤免疫治疗近年来取得重大突破，然而约10%的患者会发生治疗后疾病超进展现象，其发生的机制尚不明确。调节性T细胞（Treg）作为最重要的免疫调节细胞，在肿瘤免疫治疗超进展中发挥的作用尚未有报道。目前期研究发现，肿瘤组织中Treg细胞高表达PD-1,且超进展的患者治疗前体内的Treg细胞比例较非超进展患者更高，并且治疗后，超进展患者肿瘤组织局部的Treg细胞的比例会进一步升高。据此推断：抗PD-1抗体促进Treg细胞增值并且增强了Treg细胞抑制能力，是导致肿瘤迅速进展的原因之一。本项目拟利用临床样本分析和探索抗PD-1抗体对Treg细胞的影响，并利用生物信息学及体外实验进一步探讨抗PD-1抗体对肿瘤微环境中Treg细胞作用的具体分子机制，最后通过统计临床病例特点，分析超进展患者的临床特征通过本项目，不但能够阐明Treg细胞在超进展现象中的作用及其潜在机制，而且能够为抗肿瘤免疫提供新思路。

肿瘤免疫治疗近年来取得重大突破，然而约10%的患者会发生治疗后超进展现象，其严重影响患者的预后。肿瘤免疫治疗超进展的发生的机制目前尚不明确，对于超进展患者的临床特征的描述、分析及构建预测模型对免疫治疗的临床应用意义重大，对发生超进展的肿瘤微环境的描述也有助于阐明超进展的具体机制。本项目利用回顾性研究筛选出临床接受免疫治疗后发生超进展的患者，明确免疫治疗超进展患者的临床特征及预后相关因素；利用超进展患者的肿瘤组织石蜡切片及新鲜外周血及组织对照标本，部分阐明了发生超进展的肿瘤组织的基因、免疫特征；通过分析超进展患者的独立预后因素，建立了具有良好预测超进展患者能力的nomogram模型。通过本项目，不但能够进一步明确超进展患者的临床及生物学特征，而且能够为免疫治疗超进展的筛选提供新的证据和思路。