DNA 甲基转移酶抑制剂地西他滨联合抗 PD-1 (DP) 联合疗法对复发/难治性经典霍奇金淋巴瘤 (cHL) 有效。然而，一部分患者在 DP 治疗后出现原发性耐药或复发/进展。在这项研究中，我们评估了由组蛋白脱乙酰酶抑制剂西达本胺、地西他滨和抗 PD-1 卡瑞利珠单抗 (CDP) 组成的三联疗法对 52 名既往接受过 DP 治疗的复发/难治性 cHL 患者的疗效和安全性 (NCT04233294) 。 CDP 治疗耐受性良好，客观缓解率为 94%（95% CI，84-99%），其中 50%（95% CI，36-64%）的患者达到完全缓解 (CR)。值得注意的是，所有对先前 DP 治疗有抵抗力的患者在 CDP 治疗后均表现出治疗反应，尽管他们的 CR 率低于对先前 DP 治疗有反应的患者。总体而言，CDP 治疗后的中位无进展生存期为 29.4 个月。通过对治疗前和治疗中 cHL 肿瘤活检组织进行单细胞 RNA 测序，我们观察到罕见恶性霍奇金里德/斯腾伯格 (HRS) 样细胞的异质性。经典的 CD30 HRS 样细胞与丰富的免疫抑制性 IL21 CD4 T 辅助细胞相互作用，形成支持其生存的正反馈循环。相比之下，CD30-HRS样细胞群表现出对抗PD-1免疫疗法的潜在抵抗力。 CDP治疗促进多种肿瘤反应性CD8 T细胞的激活，并通过抑制STAT1/3信号传导抑制IL21 CD4 T细胞的增殖，从而减轻其免疫抑制作用。这些发现提供了对导致抗 PD-1 耐药性的 cHL 微环境的见解，并强调了双重表观免疫疗法在克服免疫治疗耐药性方面的治疗效果。版权所有 © 2024 美国血液学会。

DNA methyltransferase inhibitor decitabine plus anti-PD-1 (DP) combination therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine and anti-PD-1 camrelizumab (CDP) in 52 patients with relapsed/refractory cHL who had previously received DP therapy (NCT04233294). CDP treatment was well-tolerate and resulted in an objective response rate of 94% (95% CI, 84-99%), with 50% (95% CI, 36-64%) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses following CDP therapy, although their CR rate was lower compared to patients responsive to prior DP. Overall, the median progression-free survival following CDP therapy was 29.4 months. Through single-cell RNA sequencing of pre-treatment and on-treatment cHL tumor biopsies, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with the abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. In contrast, the CD30- HRS-like cell population showed potential resistance to anti-PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti-PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance.Copyright © 2024 American Society of Hematology.