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。

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.