文章：

霍奇金淋巴瘤及其他血液恶性肿瘤中的免疫检查点分子

Immune Checkpoint Molecules in Hodgkin Lymphoma and Other Hematological Malignancies

原文发布日期：10 July 2025

DOI: 10.3390/cancers17142292

类型: Article

开放获取: 是

英文摘要：

Immune checkpoints such as PD-1/PD-L1, CTLA-4, LAG-3, TIM-3, and TIGIT play critical roles in regulating anti-tumor immunity and are exploited by hematological malignancies to evade immune surveillance. While classic Hodgkin lymphoma (HL) demonstrates notable responsiveness to immune checkpoint inhibitors (ICIs), which is attributed to genetic alterations like chromosome 9p24.1 amplification, the responsiveness of non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM) remain inconsistent and generally modest. In NHL, the heterogeneous immune microenvironment, particularly variations in tumor-infiltrating lymphocytes and PD-L1 expression, drives differential ICI outcomes. AML shows limited responsiveness to monotherapy, but the combination of monotherapy with hypomethylating agents yield encouraging results, particularly in selected patient subsets. Conversely, MM trials have largely failed, potentially due to genetic polymorphisms influencing checkpoint signaling pathways and the inherently immunosuppressive bone marrow microenvironment. Both intrinsic tumor factors (low tumor mutational burden, impaired antigen presentation, IFN-γ pathway alterations) and extrinsic factors (immunosuppressive cells and alternative checkpoint upregulation) contribute significantly to primary and acquired resistance mechanisms. Future strategies to overcome resistance emphasize combination therapies, such as dual checkpoint blockade, epigenetic modulation, and reprogramming the tumor microenvironment, as well as biomarker-driven patient selection, aiming for precision-based, tailored immunotherapy across hematological malignancies.

摘要翻译： 

PD-1/PD-L1、CTLA-4、LAG-3、TIM-3及TIGIT等免疫检查点在调控抗肿瘤免疫中发挥关键作用，并被血液系统恶性肿瘤利用以逃避免疫监视。经典霍奇金淋巴瘤（HL）对免疫检查点抑制剂（ICIs）表现出显著的治疗反应，这主要归因于9p24.1染色体扩增等遗传学改变；然而，非霍奇金淋巴瘤（NHL）、急性髓系白血病（AML）和多发性骨髓瘤（MM）对ICIs的反应仍不一致且总体有限。在NHL中，异质性的免疫微环境，特别是肿瘤浸润淋巴细胞和PD-L1表达的差异，导致了ICI疗效的异质性。AML对单药ICI治疗反应有限，但联合去甲基化药物在特定患者亚群中显示出令人鼓舞的疗效。相比之下，MM的ICI临床试验大多未能成功，可能与影响检查点信号通路的基因多态性及骨髓固有的免疫抑制微环境有关。内在肿瘤因素（低肿瘤突变负荷、抗原提呈功能受损、IFN-γ通路改变）和外在因素（免疫抑制细胞及替代性检查点上调）共同构成了原发性和获得性耐药的重要机制。未来克服耐药性的策略将侧重于联合疗法，如双检查点阻断、表观遗传调控及肿瘤微环境重编程，同时结合生物标志物驱动的患者筛选，旨在实现针对血液系统恶性肿瘤的精准化、个体化免疫治疗。

原文链接：

Immune Checkpoint Molecules in Hodgkin Lymphoma and Other Hematological Malignancies