God Jason M, Amria Shereen, Cameron Christine A, Zhang Lixia, Bethard Jennifer R, Haque Azizul
Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
Cells. 2025 Aug 7;14(15):1220. doi: 10.3390/cells14151220.
B-cell lymphomas, including Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL), evade CD4+ T-cell immunity through novel HLA class II-associated immunosuppressive mechanisms. Despite expressing surface HLA-DR, these tumors fail to activate antigen-specific CD4+ T cells, independent of co-stimulation or PD-L1 checkpoint inhibition. We identified lymphoma-secreted factors that broadly disrupt HLA class II-mediated antigen presentation in both malignant B cells and dendritic cells (DCs), silencing T-cell responses. This inhibition is allele-independent (affecting DR1, DR4, DR7) but spares HLA class I-mediated CD8+ T-cell recognition, indicating a targeted immune evasion strategy. Biochemical and mass spectrometry (MALDI-MS) analyses revealed unique low-molecular-weight peptides (693-790 Da) in BL cells, absent in normal B cells, which may mediate this suppression. Functional fractionation confirmed bioactive inhibitory fractions in lymphoma lysates, further implicating tumor-intrinsic molecules in immune escape. These findings highlight a previously unrecognized axis of B-cell lymphoma immune evasion, where secreted factors disable HLA class II function across antigen-presenting cells. Therapeutically, neutralizing these immunosuppressive molecules could restore CD4+ T-cell surveillance and enhance immunotherapies in B-cell malignancies. This work underscores the importance of HLA class II dysfunction in lymphoma progression and identifies candidate targets for reversing immune suppression.
B细胞淋巴瘤，包括伯基特淋巴瘤（BL）、弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL），通过新的HLA II类相关免疫抑制机制逃避CD4+ T细胞免疫。尽管这些肿瘤表达表面HLA-DR，但它们无法激活抗原特异性CD4+ T细胞，这与共刺激或程序性死亡配体1（PD-L1）检查点抑制无关。我们鉴定出淋巴瘤分泌的因子，这些因子广泛破坏恶性B细胞和树突状细胞（DC）中HLA II类介导的抗原呈递，从而使T细胞反应沉默。这种抑制不依赖于等位基因（影响DR1、DR4、DR7），但不影响HLA I类介导的CD8+ T细胞识别，表明这是一种有针对性的免疫逃逸策略。生化和基质辅助激光解吸电离质谱（MALDI-MS）分析显示，BL细胞中存在正常B细胞中不存在的独特低分子量肽（693-790道尔顿），这些肽可能介导这种抑制作用。功能分级分离证实淋巴瘤裂解物中存在生物活性抑制级分，进一步表明肿瘤内在分子参与免疫逃逸。这些发现突出了B细胞淋巴瘤免疫逃逸中一个以前未被认识的轴，即分泌的因子使抗原呈递细胞中的HLA II类功能失效。在治疗方面，中和这些免疫抑制分子可以恢复CD4+ T细胞监测，并增强B细胞恶性肿瘤的免疫治疗。这项工作强调了HLA II类功能障碍在淋巴瘤进展中的重要性，并确定了逆转免疫抑制的候选靶点。
