Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.

IF 28.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2025-10-03 DOI:10.1038/s43018-025-01054-6

Carl Sandén, Niklas Landberg, Pablo Peña-Martínez, Hanna Thorsson, Shruti Daga, Noelia Puente-Moncada, Maria Rodriguez-Zabala, Sofia von Palffy, Marianne Rissler, Vladimir Lazarevic, Gunnar Juliusson, Mats Ohlin, Axel Hyrenius-Wittsten, Christina Orsmark-Pietras, Henrik Lilljebjörn, Helena Ågerstam, Thoas Fioretos

{"title":"Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.","authors":"Carl Sandén, Niklas Landberg, Pablo Peña-Martínez, Hanna Thorsson, Shruti Daga, Noelia Puente-Moncada, Maria Rodriguez-Zabala, Sofia von Palffy, Marianne Rissler, Vladimir Lazarevic, Gunnar Juliusson, Mats Ohlin, Axel Hyrenius-Wittsten, Christina Orsmark-Pietras, Henrik Lilljebjörn, Helena Ågerstam, Thoas Fioretos","doi":"10.1038/s43018-025-01054-6","DOIUrl":null,"url":null,"abstract":"<p><p>Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.</p>","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":" ","pages":""},"PeriodicalIF":28.5000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s43018-025-01054-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.

查看原文本刊更多论文

在急性髓系白血病中，SLAMF6的异常表达构成了一种可靶向的免疫逃逸机制。

免疫治疗在急性髓性白血病（AML）中显示出有限的成功，表明对潜在的免疫调节机制的理解不完整。在这里，我们发现60%的AML病例中存在一种免疫逃避机制，其中原始AML细胞异常表达淋巴样表面蛋白SLAMF6（信号淋巴细胞激活分子家族成员6）。敲除AML细胞中的SLAMF6能够激活T细胞并在共培养系统中高效杀死白血病细胞，这表明SLAMF6以类似于程序性细胞死亡蛋白-配体（PDL1/PD1）轴的模式保护AML细胞免受免疫系统的识别和消除。在体外和人源化的体内模型中，用针对SLAMF6二聚化位点的抗体靶向SLAMF6可抑制SLAMF6-SLAMF6相互作用，诱导T细胞活化和杀伤AML细胞。总之，我们表明SLAMF6的异常表达是一种常见的、可靶向的免疫逃逸机制，可以为AML的免疫治疗铺平道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.