髓系抑制性细胞（MDSCs）介导的低剂量地西他滨逆转上皮源肿瘤PD-1抑制剂抵抗的机制与临床研究

Blockage of immune regulatory checkpoint PD-1 is at the forefront of immunotherapy for cancers of various histological types. However, PD-1 blockage fails to control neoplasia in a significant proportion of patients due to primary and acquired resistance. It is well demonstrated that myeloid-derived suppressor cells and other factors operating within the tumor immunosuppressive microenvironment play the critical roles in inhibition of the therapeutic activities of PD-1 blockage. Accumulating evidence indicates that epigenetic regulation underlies MDSCs accumulation and functions, providing the theoretical basis for the combination of hypomethylating agent decitabine and PD-1 blockage. We have registered the clinical trial in the ClinicalTrials.gov database (identifier NCT02961101) to determine the safety and efficacy of cotreatment of low-dose decitabine and PD-1 blockage in patients with relapsed/refractory malignancies. The clinical benefit has been confirmed in 9/11 patients with PD-1 blockage resistant, relapsed/refractory malignancies, suggesting that low-dose decitabine could prevent or reverse non-responsiveness to PD-1 blockage. Therefore, we aim to confirm the subvertion effect of low-dose decitabine on resistance to PD-1 blockage via MDSCs, to illustrate the molecular mechanism of suppression of MDSCs and reverse of resistance to PD-1 blockage by decitabine, and to establish and optimize the regimen of low-dose dicitabine combined with PD-1 blockage in patients with PD-1 blockage resistant, relapsed/refractory epitheliogenic malignancies, and to evaluate the feasibility of circulatory MDSCs as an efficacy marker.

免疫检验点PD-1抑制剂在肿瘤治疗中取得了突破性进展，但耐药性严重制约了其临床应用。大量研究表明髓系抑制性细胞（MDSCs）等肿瘤免疫抑制性微环境可能是介导PD-1抑制剂耐药的关键因素，而MDSCs的生长与积聚均受到表观遗传的调控，为去甲基化药物地西他滨与PD-1抑制剂联合应用提供了理论基础。本团队率先注册了低剂量地西他滨联合PD-1抑制剂方案的国际临床试验，前期9/11例PD-1抑制剂抵抗的复发、难治性晚期肿瘤患者获得了明确的临床疗效，提示低剂量地西他滨可改善/逆转PD-1抑制剂耐药。基于此，本课题拟从动物模型和临床角度验证低剂量地西他滨逆转MDSCs介导的PD-1抑制剂耐药的效果，从分子、细胞及整体水平阐明地西他滨通过抑制MDSCs逆转PD-1抑制剂耐药的关键机制，并建立优化的低剂量地西他滨联合PD-1抑制剂治疗复发、难治上皮源肿瘤的整体方案与循环MDSCs作为疗效评估指标的可行性。

髓系抑制性细胞（MDSCs）等天然免疫细胞介导的肿瘤免疫抑制性微环境是制约PD-1抑制剂临床疗效的关键因素。本课题拟从多角度、多层面分析地西他滨改善免疫微环境、调控肿瘤免疫治疗疗效的作用机制，并进一步探索临床转化可行性。研究依托临床样本，从甲基化谱和转录谱层面证实了地西他滨对T细胞的直接调控作用，证实其可增加肿瘤微环境T细胞浸润，并初步筛选了可能的关键效应分子。随后利用地西他滨同类药物，开展了吉西他滨化疗联合PD-1 抑制剂方案治疗复发难治性和进展期肿瘤的多项临床试验，临床疗效提高2 倍以上，有效延长了患者的无进展生存期 (PFS)和总生存期 (OS)，其中GVD联合PD-1抗体治疗rrPMBCL的完全缓解率高达56%，方案入选2021年CSCO淋巴瘤诊疗指南。通过外周血免疫细胞活性监测系统分析，明确了外周循环M-MDSC和多种血清炎症相关因子（IL-6、IL-10、IFNγ、IL-8等）作为疗效预判标志物的可行性。进一步解析了天然免疫激动剂通过调控天然免疫细胞靶点发挥抗肿瘤免疫作用机理，开展联合PD-1抑制剂方案治疗复发难治性实体瘤的I期临床转化探索，取得突破性疗效，结果入选2020年中国学者十大免疫学研究进展。本课题研究结果为改善肿瘤免疫微环境、提高免疫治疗临床疗效提供新的思路和方案，并且为探索新的天然免疫临床治疗靶点提供研究基础。本课题相关结果发表SCI论文4篇，总影响因子59.3，10分以上3篇，单篇最高25.6。