Michelle Sætersmoen, Ivan S Kotchetkov, Lamberto Torralba-Raga, Jorge Mansilla-Soto, Ebba Sohlberg, Silje Zandstra Krokeide, Quirin Hammer, Michel Sadelain, Karl-Johan Malmberg
{"title":"利用 NKG2A/C 转换受体靶向 HLA-E 表达过高的癌症。","authors":"Michelle Sætersmoen, Ivan S Kotchetkov, Lamberto Torralba-Raga, Jorge Mansilla-Soto, Ebba Sohlberg, Silje Zandstra Krokeide, Quirin Hammer, Michel Sadelain, Karl-Johan Malmberg","doi":"10.1016/j.medj.2024.09.010","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A<sup>+</sup> CD8<sup>+</sup> T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells.</p><p><strong>Methods: </strong>We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma.</p><p><strong>Findings: </strong>A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression.</p><p><strong>Conclusions: </strong>The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.</p><p><strong>Funding: </strong>This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor.\",\"authors\":\"Michelle Sætersmoen, Ivan S Kotchetkov, Lamberto Torralba-Raga, Jorge Mansilla-Soto, Ebba Sohlberg, Silje Zandstra Krokeide, Quirin Hammer, Michel Sadelain, Karl-Johan Malmberg\",\"doi\":\"10.1016/j.medj.2024.09.010\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A<sup>+</sup> CD8<sup>+</sup> T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells.</p><p><strong>Methods: </strong>We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma.</p><p><strong>Findings: </strong>A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression.</p><p><strong>Conclusions: </strong>The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.</p><p><strong>Funding: </strong>This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute.</p>\",\"PeriodicalId\":29964,\"journal\":{\"name\":\"Med\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Med\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.medj.2024.09.010\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2024.09.010","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
背景:人类白细胞抗原(HLA)-E在包括恶性胶质母细胞瘤在内的大部分实体瘤中过度表达,是肿瘤微环境和血液循环中NKG2A+ CD8+ T细胞和自然杀伤(NK)细胞的主要检查点。该轴与 PD-L1 一起抑制 T 细胞和 NK 细胞的效应反应:我们设计了一种嵌合 A/C 开关受体,它结合了 NKG2A 受体外结构域的高 HLA-E 结合亲和力和 NKG2C 受体内结构域的激活信号。针对不同HLA-E表达水平的肿瘤细胞,评估了经A/C转换的NK和T细胞的细胞毒功能。使用胶质母细胞瘤异种移植模型评估了体内疗效:A/C转换诱导的NK和T细胞对HLA-E中高表达的肿瘤细胞具有卓越的特异性细胞毒性。在胶质母细胞瘤异种移植模型中,A/C转换表达的人类T细胞表现出更强的抗肿瘤功能。改良T细胞的活性受A/C转换水平和HLA-E表达之间平衡的制约,从而创造了一个治疗窗口,最大限度地减少靶上毒性和瘤外毒性。即使在干扰素(IFN)-γ预处理以诱导HLA-E表达后,正常细胞仍对A/C转换T细胞不敏感:结论:A/C转换受体可单独或与其他特异性结合,有效靶向表达高水平HLA-E的肿瘤细胞,从而克服NKG2A/HLA-E检查点的抑制作用。这种方法为靶向HLA-E高表达肿瘤提供了一种安全性良好、前景广阔的治疗策略:这项工作由挪威研究理事会、挪威癌症协会和国家癌症研究所资助。
Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor.
Background: Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A+ CD8+ T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells.
Methods: We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma.
Findings: A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression.
Conclusions: The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.
Funding: This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute.
期刊介绍:
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.