PD-1抗体已批准用于多种肿瘤，治疗霍奇金淋巴瘤（cHL）疗效最好，但仅不足25%患者可完全缓解。疗效预测生物标志物及新型联合治疗抗肿瘤机理的探索成为研究重点。鉴于DNA去甲基化药物地西他滨对T细胞活性调控作用，本团队国内首先注册开展低剂量地西他滨联合PD-1抗体治疗复发难治性恶性肿瘤临床试验。前期结果表明联合治疗显著提高cHL患者完全缓解率，并可克服PD-1抗体抵抗。血清学检测提示EGF、VEGF本底水平及其变化趋势与联合治疗反应性相关，因而提出肿瘤血管发生及免疫微环境调控可能参与PD-1抑制剂抗瘤作用的假说。本项目从血清细胞因子水平深入分析地西他滨与PD-1抗体联合治疗敏感性相关指标，从细胞、小鼠及临床样本多层面检测EGF、VEGF及其信号通路在PD-1抗体及联合治疗中的调控作用，解析肿瘤血管生成、免疫微环境与免疫治疗反应性之间的关联，建立PD-1抗体联合治疗评估体系及最优临床方案。

Anti-PD-1 antibodies have been approved in treatment with various tumor types, although patients with relapsed/refractory classical Hodgkin’s lymphoma (r/r cHL) having the highest clinical response, anti-PD-1 monotherapy can induce complete remission only in less than 25% patients. It is of vital importance to identify prognosis biomarkers and novel efficient combination strategy with PD-1 inhibitor. Based on the observation that DNA demethylating agent could enhance T cell activity, our team firstly registered in China and performed clinical trials of low-dose decitabine combined anti-PD-1 antibody in relapsed or refractory malignancies. These preliminary data has shown that decitabine-primed anti-PD-1 could induce prominent complete response in patients with r/r cHL, and outcome the resistance to anti-PD-1 monotherapy. The serum cytokine level detection indicated that the baseline and alteration of EGF, VEGF levels might be associated with the clinical response of decitabine-plus-anti-PD-1 combination therapy. Thus, we proposed hypothesis that the regulation of tumor angiogenesis and tumor microenvironment would be beneficial to PD-1 blockade in r/r cHL. In this program, we will first analyze the relationship between serum cytokine levels and therapeutic benefit of decitabine-plus-anti-PD-1 combination treatment, and detect the function of EGF, VEGF signaling in PD-1 blockade as well as combination therapy from various aspects, to explore the association of tumor angiogenesis/immune microenvironment/immune checkpoint blockade, and finally establish the prognosis system and optimal clinical strategy.