PO.TB10.09 · 肿瘤生物学
嗜酸性粒细胞促进多发性骨髓瘤中免疫抑制性的骨髓微环境
Eosinophils promote an immunosuppressive bone marrow microenvironment in multiple myeloma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
多发性骨髓瘤（MM）是一种无法治愈的恶性肿瘤，其特征为骨髓内浆细胞的扩增，导致结构破坏、溶骨性病变以及深度免疫失调。尽管治疗进展改善了初始反应，但几乎所有患者最终都会发展为复发或难治性疾病。理解驱动肿瘤免疫逃逸和MM进展的细胞机制仍是一项关键的未满足需求，尤其是当患者成为细胞疗法（CAR-T）或T细胞衔接器（TCEs）候选者时，这些疗法目前实现的中位无进展生存期仅约1年。这种有限的持久性在很大程度上归因于MM诱导的免疫抑制微环境和T细胞耗竭。因此，识别骨髓内免疫抑制的细胞介导者对于提高免疫疗法的疗效至关重要。为弥补这一知识空白，我们利用空间转录组学（10x Visium）以无偏倚的方式探究MM骨髓微环境，揭示了嗜酸性粒细胞在荷MM小鼠的肿瘤床内富集。嗜酸性粒细胞此前从未在MM中被研究过，并且由于其不稳定的性质和高RNA酶含量，在scRNA-seq数据集中代表性不足。为检验嗜酸性粒细胞的功能作用，我们使用了一种同基因MM模型（5TGM1细胞植入免疫健全的C57BL/6-KaLwRij小鼠），该模型再现了人类疾病的关键特征。我们发现，在MM建立之前清除嗜酸性粒细胞（alpha-SiglecF抗体；腹腔注射）可显著减少体内肿瘤生长。随后我们比较了KaLwRij小鼠与C57BL/6 RAG2（B和T细胞缺陷）小鼠，观察到嗜酸性粒细胞介导的MM进展需要完整的适应性免疫系统。使用流式细胞术，我们确定嗜酸性粒细胞清除可减少CD8⁺ T细胞耗竭（TIM-3⁺ PD-1⁺），同时增强T细胞活化（CD69⁺ CD25⁺）。在体外，我们使用原代嗜酸性粒细胞，发现暴露于5TGM1 MM细胞足以诱导嗜酸性粒细胞PD-L1表达。我们还观察到经MM教育的嗜酸性粒细胞可在预活化的CD8 T细胞中诱导耗竭（PD1+ CTLA4+）。总之，我们的发现将嗜酸性粒细胞确定为MM骨髓微环境中此前未被认识的免疫抑制介导者，并强调其作为增强现有免疫疗法持久性的潜在治疗靶点。
查看英文原文 English abstract
Multiple Myeloma (MM) is an incurable malignancy characterized by the expansion of plasma cells within the bone marrow, leading to structural disruption, osteolytic lesions, and profound immune dysregulation. Although therapeutic advances have improved initial responses, nearly all patients eventually develop relapsed or refractory disease. Understanding the cellular mechanisms that drive tumor immune escape and MM progression remains a critical unmet need, particularly as patients become candidates for cellular therapies (CAR-T) or T-cell engagers (TCEs), which currently achieve a median progression-free survival of only ~1 year. This limited durability is largely attributed to the MM-induced immunosuppressive microenvironment and T-cell exhaustion. Identifying cellular mediators of immunosuppression within the bone marrow is therefore essential to improving the efficacy of immunotherapies.To address this gap in knowledge we leveraged spatial transcriptomics (10x Visium) to interrogate the MM bone marrow microenvironment in an unbiased manner and revealed that eosinophils are enriched within the tumor bed of MM-bearing mice. Eosinophils have not previously been investigated in MM and are underrepresented in scRNA-seq datasets due to their labile nature and high RNAase content. To test the functional role of eosinophils, we used a syngeneic MM model (5TGM1 cells in immunocompetent C57BL/6-KaLwRij mice) that recapitulates key features of human disease. We found that depletion of eosinophils (alpha-SiglecF antibody; IP) prior to the establishment of MM significantly reduces tumor growth in vivo . We then compared KaLwRij versus C57BL/6 RAG2 (B and T cell deficient) mice and observed that eosinophil-mediated MM progression requires an intact adaptive immune system. Using flow cytometry, we determined that eosinophil depletion decreases CD8⁺ T-cell exhaustion (TIM-3⁺ PD-1⁺) while enhancing T-cell activation (CD69⁺ CD25⁺). In vitro , we used primary eosinophils and found that exposure to 5TGM1 MM cells is sufficient to induce eosinophil PD-L1 expression. We also observed that MM-educated eosinophils can induce exhaustion (PD1+ CTLA4+) in pre-activated CD8 T cells.Together, our findings identify eosinophils as previously unrecognized mediators of immunosuppression in the MM bone marrow microenvironment and highlight them as a potential therapeutic target to enhance the durability of existing immunotherapies.
利益披露 Disclosure
H. du Bois, None..
A. Chaves, None..
D. Atta, None..
M. Nasr, None.