PD-1抗体的诞生使超过80%复发难治性经典型霍奇金淋巴瘤（r/r CHL）患者临床获益，但不足30%的完全缓解（CR）率仍难以给患者良好预后。研究表明DNA甲基化会导致T细胞耗竭，限制PD-1抗体疗效。本团队率先注册开展了低剂量DNA去甲基化药物地西他滨联合PD-1抗体治疗r/r cHL临床试验，前期结果表明此联合方案能够显著提高PD-1抗体的CR率，患者外周T细胞活性增强，且发现联合治疗后CD4/CD8比值升高。霍奇金淋巴瘤具有独特的肿瘤微环境，CD4 T细胞大量富集且RS肿瘤细胞I型MHC分子表达频繁缺失，提示非CD8 T细胞也参与PD-1抗体诱导的免疫应答。因此，我们提出地西他滨通过调控CD4效应T细胞活性而增强PD-1抗体临床疗效的假说，并将从细胞水平、动物模型及临床样本多层面探讨地西他滨、PD-1抗体及二者联合对CD4 T细胞的调控效应，建立预后评估体系。

Anti-programmed death-1 (PD-1) antibody induces more than 80% clinical response in relapsed/refractory classical Hodgkin's lymphoma (R/R cHL), but less than 30% complete remission (CR) is observed. Improving the CR rate of anti-PD-1 antibody and disease prognosis is still a significant issue to be solved urgently. It is demonstrated that de novo DNA methylation promoted T-cell exhaustion and limited the effect of anti-PD-1 antibody. We first have registered the clinical trial in the ClinicalTrials.gov database to determine the safety and efficacy of low-dose decitabine-plus-anti-PD-1 antibody in patients with R/R cHL. Preliminary results showed that the addition of decitabine could significantly improve the CR rate of anti-PD-1 antibody, enhance the activity of CD3+ T cells and increase the ratio of CD4/CD8 in peripheral blood. CHL is characterized by an abundance of CD4+ T cells in tumor microenvironment, and the expression of major histocompatibility complex class I (MHC I) in RS tumor cells is frequently absent, suggesting that non-CD8 T cells are also involved in the immune response induced by anti-PD-1 antibody. Therefore, we propose the hypothesis that decitabine enhances the effect of anti-PD-1 antibody by regulating CD4 effector T cells activation, and aim to explore the effect of decitabine, anti-PD-1 antibody as well as combined regimen on the proliferation, activation, differentiation, cytotoxicity and exhaustion of CD4 T cells, to investigate the molecular mechanism of T cells activation by the combined therapy, and to establish optimized regimen of low-dose demethylating agent combined with an-PD-1 antibody in R/R cHL patients.