美国麻省理工学院Robert T. Manguso研究组发现，靶向氨基肽酶ERAP通过破坏NKG2A-HLA-E抑制性检查点增强抗肿瘤免疫。相关论文于2024年11月18日在线发表于国际学术期刊《免疫》。

研究人员表示，氨基肽酶内质网氨基肽酶1（ERAP1）负责修剪肽段，以便将其加载到主要组织相容性复合物I类（MHC class I）中，而这种活性的丧失对MHC class I肽组有广泛影响。

研究人员揭示了靶向ERAP1在免疫检查点抑制（ICB）中的作用，因为MHC class I相互作用在抗肿瘤免疫中既发挥激活作用，也具有抑制作用。ERAP1的缺失使小鼠肿瘤模型对ICB更为敏感，而这种敏感性依赖于CD8⁺ T细胞和自然杀伤（NK）细胞。

体内抑制筛选显示，Erap1缺失激活了抑制性NKG2A-HLA-E检查点，这需要HLA-E上呈递一组有限的不变表位（VL9）。ERAP的缺失改变了HLA-E肽组，防止了NKG2A的结合。在人类中，ERAP1和ERAP2在VL9的处理和呈递上具有功能冗余，而两者的丧失会使癌细胞中的NKG2A检查点失活。

因此，ERAP的缺失模拟了NKG2A-HLA-E通路的抑制，代表了一种有前景的靶向这一关键检查点的方法。

附：英文原文

Title: Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint

Author: Hsiao-Wei Tsao, Seth Anderson, Kenneth J. Finn, Jonathan J. Perera, Lomax F. Pass, Emily M. Schneider, Aiping Jiang, Rachel Fetterman, Cun Lan Chuong, Kaiya Kozuma, Marcia M. Stickler, Marc Creixell, Susan Klaeger, Kshiti Meera Phulphagar, Suzanna Rachimi, Eva K. Verzani, Niclas Olsson, Juan Dubrot, Matthew F. Pech, Whitney Silkworth, Sarah Kate Lane-Reticker, Peter M. Allen, Kyrellos Ibrahim, Nelson H. Knudsen, Andrew Y. Cheng, Adrienne H. Long, Hakimeh Ebrahimi-Nik, Sarah Y. Kim, Peter P. Du, Arvin Iracheta-Vellve, Emily J. Robitschek, Juliette S.M.T. Suermondt, Thomas G.R. Davis, Clara H. Wolfe, Trisha Atluri, Kira E. Olander, Jason S. Rush, Thomas B. Sundberg, Fiona E. McAllister, Jennifer G. Abelin, Ari Firestone, David Stokoe, Steven A. Carr, Fiona A. Harding, Kathleen B. Yates, Robert T. Manguso

Issue&Volume: 2024-11-18

Abstract: The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8+ T cells and natural killer (NK) cells. In vivo suppression screens revealed that Erap1 deletion inactivated the inhibitory NKG2A-HLA-E checkpoint, which requires presentation of a restricted set of invariant epitopes (VL9) on HLA-E. Loss of ERAP altered the HLA-E peptidome, preventing NKG2A engagement. In humans, ERAP1 and ERAP2 showed functional redundancy for the processing and presentation of VL9, and loss of both inactivated the NKG2A checkpoint in cancer cells. Thus, loss of ERAP phenocopies the inhibition of the NKG2A-HLA-E pathway and represents an attractive approach to inhibit this critical checkpoint.

DOI: 10.1016/j.immuni.2024.10.013

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00493-X