表观遗传学药物加抗 PD-1 重塑肿瘤微环境并恢复霍奇金淋巴瘤的抗肿瘤疗效

IF 21 1区 医学 Q1 HEMATOLOGY Blood Pub Date : 2024-10-31 DOI:10.1182/blood.2024024487
Jing Nie, Chunmeng Wang, Liangtao Zheng, Yang Liu, Chengcheng Wang, Yixin Chang, Yudi Hu, Bing Guo, Yuting Pan, Qingming Yang, Xueda Hu, Weidong Han
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引用次数: 0

摘要

DNA甲基转移酶抑制剂地西他滨+抗PD-1(DP)联合疗法对复发/难治性典型霍奇金淋巴瘤(cHL)有效。然而,一部分患者在接受DP治疗后出现了原发性耐药或复发/进展。在这项研究中,我们评估了由组蛋白去乙酰化酶抑制剂奇达胺、地西他滨和抗PD-1康瑞珠单抗(CDP)组成的三联疗法在52例既往接受过DP治疗的复发/难治性cHL患者中的疗效和安全性(NCT04233294)。CDP治疗效果良好,客观反应率为94%(95% CI,84-99%),其中50%(95% CI,36-64%)的患者获得了完全反应(CR)。值得注意的是,所有对既往DP治疗不耐受的患者在接受CDP治疗后都表现出了治疗反应,尽管与对既往DP治疗有反应的患者相比,他们的CR率较低。总体而言,CDP疗法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的cHL肿瘤活检组织进行单细胞RNA测序,我们观察到了罕见恶性霍奇金里德/斯特恩伯格(HRS)样细胞的异质性。典型的CD30+ HRS样细胞与大量免疫抑制性IL21+CD4+ T辅助细胞相互作用,形成正反馈循环,支持其生存。相比之下,CD30- HRS样细胞群对抗PD-1免疫疗法表现出潜在的抵抗力。CDP治疗可促进多种肿瘤反应性CD8+ T细胞的活化,并通过抑制STAT1/3信号传导抑制IL21+CD4+ T细胞的增殖,从而减轻它们的免疫抑制作用。这些发现深入揭示了导致抗PD-1耐药的cHL微环境,并凸显了双重外免疫疗法在克服免疫疗法耐药方面的疗效。
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Epigenetic agents plus anti-PD-1 reprogram the tumor microenvironment and restore antitumor efficacy in Hodgkin lymphoma.

Abstract: DNA methyltransferase inhibitor decitabine plus anti-programmed cell death 1 (DP) 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 who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [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 after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. While 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. This trial was registered at www.clinicaltrials.gov as #NCT04233294.

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来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
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