儿科经典霍奇金淋巴瘤（cHL）患者的生存率很高，但会遭受化疗和放疗引起的严重的长期副作用。 cHL 肿瘤的特点是肿瘤中恶性霍奇金细胞和里德-斯滕伯格 (HRS) 细胞的比例较低 (0.1%-10%)。 HRS 细胞的生存和生长依赖于周围的免疫细胞。目前针对 cHL 肿瘤中 PD-1/PD-L1 轴的治疗方法充分利用了这种依赖性。开发针对肿瘤的更具针对性的疗法，因此与传统化疗相比对健康组织的毒性较小，可以改善儿科 cHL 幸存者的生活质量。在这里，我们对分离的 HRS 细胞和来自同一 cHL 肿瘤的免疫细胞应用了单细胞 RNA 测序 (scRNA-seq)。除了 TNFRSF8 (CD30) 之外，我们还鉴定了在 HRS 细胞中持续过度表达的其他细胞表面蛋白基因，例如 NRXN3 和 LRP8，它们有可能用作抗体药物偶联物或 CAR T 细胞的替代靶标。最后，我们确定了 HRS 细胞抑制 T 细胞的潜在相互作用，其中包括 galectin-1/CD69 和 HLA-II/LAG3 相互作用。 RNAscope 用于验证 HRS 细胞附近 T 细胞上 CD69 和 LAG3 表达的富集，并表明患者之间和肿瘤组织区域之间与相应配体的相互作用强度存在很大差异。总之，这项研究确定了 cHL 新的潜在治疗靶点，并强调了在确定治疗靶点时研究异质性的重要性，特别是那些针对肿瘤-免疫细胞相互作用的治疗靶点。© 2024 作者。约翰·威利 (John Wiley) 出版的 HemaSphere

Pediatric classic Hodgkin lymphoma (cHL) patients have a high survival rate but suffer from severe long-term side effects induced by chemo- and radiotherapy. cHL tumors are characterized by the low fraction (0.1%-10%) of malignant Hodgkin and Reed-Sternberg (HRS) cells in the tumor. The HRS cells depend on the surrounding immune cells for survival and growth. This dependence is leveraged by current treatments that target the PD-1/PD-L1 axis in cHL tumors. The development of more targeted therapies that are specific for the tumor and are therefore less toxic for healthy tissue compared with conventional chemotherapy could improve the quality of life of pediatric cHL survivors. Here, we applied single-cell RNA sequencing (scRNA-seq) on isolated HRS cells and the immune cells from the same cHL tumors. Besides TNFRSF8 (CD30), we identified other genes of cell surface proteins that are consistently overexpressed in HRS cells, such as NRXN3 and LRP8, which can potentially be used as alternative targets for antibody-drug conjugates or CAR T cells. Finally, we identified potential interactions by which HRS cells inhibit T cells, among which are the galectin-1/CD69 and HLA-II/LAG3 interactions. RNAscope was used to validate the enrichment of CD69 and LAG3 expression on T cells near HRS cells and indicated large variability of the interaction strength with the corresponding ligands between patients and between tumor tissue regions. In conclusion, this study identifies new potential therapeutic targets for cHL and highlights the importance of studying heterogeneity when identifying therapy targets, specifically those that target tumor-immune cell interactions.© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.