Tsao Hsiao-Wei, Anderson Seth, Finn Kenneth J, Perera Jonathan J, Pass Lomax F, Schneider Emily M, Jiang Aiping, Fetterman Rachel, Chuong Cun Lan, Kozuma Kaiya, Stickler Marcia M, Creixell Marc, Klaeger Susan, Phulphagar Kshiti Meera, Rachimi Suzanna, Verzani Eva K, Olsson Niclas, Dubrot Juan, Pech Matthew F, Silkworth Whitney, Lane-Reticker Sarah Kate, Allen Peter M, Ibrahim Kyrellos, Knudsen Nelson H, Cheng Andrew Y, Long Adrienne H, Ebrahimi-Nik Hakimeh, Kim Sarah Y, Du Peter P, Iracheta-Vellve Arvin, Robitschek Emily J, Suermondt Juliette S M T, Davis Thomas G R, Wolfe Clara H, Atluri Trisha, Olander Kira E, Rush Jason S, Sundberg Thomas B, McAllister Fiona E, Abelin Jennifer G, Firestone Ari, Stokoe David, Carr Steven A, Harding Fiona A, Yates Kathleen B, Manguso Robert T
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Calico Life Sciences, South San Francisco, CA, USA.
Immunity. 2024 Dec 10;57(12):2863-2878.e12. doi: 10.1016/j.immuni.2024.10.013. Epub 2024 Nov 18.
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.
氨肽酶，即内质网氨肽酶1（ERAP1），可对肽段进行修剪以便加载到主要组织相容性复合体I类分子（MHC I类分子）中，而这种活性的丧失会对MHC I类分子的肽组产生广泛影响。在此，我们研究了在免疫检查点阻断（ICB）中靶向ERAP1的影响，因为MHC I类分子的相互作用在抗肿瘤免疫中既介导激活功能也介导抑制功能。ERAP缺失使小鼠肿瘤模型对ICB敏感，且这种敏感性依赖于CD8 T细胞和自然杀伤（NK）细胞。体内抑制筛选显示，Erap1缺失使抑制性NKG2A-HLA-E检查点失活，该检查点需要在HLA-E上呈递一组受限的恒定表位（VL9）。ERAP的缺失改变了HLA-E的肽组，阻止了NKG2A的结合。在人类中，ERAP1和ERAP2在VL9的加工和呈递方面表现出功能冗余，二者均缺失会使癌细胞中的NKG2A检查点失活。因此，ERAP的缺失模拟了对NKG2A-HLA-E通路的抑制，代表了一种抑制这一关键检查点的有吸引力的方法。
