St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, SE1 9RT, UK.
School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Hospital, London, SE1 9RT, UK.
Nat Commun. 2023 Apr 25;14(1):2192. doi: 10.1038/s41467-023-37811-3.
Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.
尽管采用了标准的检查点抑制剂疗法，但仍有一半的黑色素瘤患者的治疗效果不佳。黑色素瘤相关抗原硫酸软骨素蛋白聚糖 4（CSPG4）的表达率约为 70%，因此针对 CSPG4 的有效免疫疗法可能会使许多患者受益。由于 IgE 在组织中发挥强大的免疫激活功能，我们构建了一种具有人恒定区的单克隆 IgE 抗体，该抗体可识别 CSPG4，以靶向黑色素瘤。CSPG4 IgE 可与包括转移灶在内的人类黑色素瘤结合，介导杀伤肿瘤的抗体依赖性细胞细胞毒性，并刺激表达人类 IgE Fc 受体的单核细胞向促炎表型分化。IgE 在植入了人类效应细胞的人黑色素瘤异种移植模型中显示出抗肿瘤活性，并与肿瘤微环境中巨噬细胞浸润增加、单核细胞和巨噬细胞基因特征富集以及促炎信号通路相关。IgE 延长了用自体免疫细胞重建的携带患者来源异种移植物的小鼠的存活期。在存在 CSPG4 IgE 的情况下，未在患者血液中检测到嗜碱性粒细胞的体外激活。我们的研究结果支持针对黑色素瘤的有前途的 IgE 为基础的免疫疗法。
