Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint
Hsiao‐Wei Tsao(Broad Institute), Seth Anderson(Broad Institute), Kenneth J. Finn(Enzo Life Sciences (United States)), Jonathan Perera(Broad Institute), Lomax F. Pass(Broad Institute), Emily M. Schneider(Broad Institute), Aiping Jiang(Broad Institute), Rachel A. Fetterman(Broad Institute), Cun Lan Chuong(Broad Institute), Kaiya Kozuma(Broad Institute), Marcia Stickler(Enzo Life Sciences (United States)), Marc Creixell(Enzo Life Sciences (United States)), Susan Klaeger(Broad Institute), Kshiti Meera Phulphagar(Broad Institute), Suzanna Rachimi(Broad Institute), Eva K. Verzani(Broad Institute), Niclas Olsson(Enzo Life Sciences (United States)), Juan Dubrot(Broad Institute), Matthew F. Pech(Enzo Life Sciences (United States)), Whitney Silkworth(Enzo Life Sciences (United States)), Sarah Kate Lane-Reticker(Broad Institute), Peter M. Allen(Broad Institute), Kyrellos Ibrahim(Broad Institute), Nelson H. Knudsen(Broad Institute), Andrew Y. Cheng(Broad Institute), Adrienne H. Long(Dana-Farber Cancer Institute), Hakimeh Ebrahimi-Nik(Broad Institute), Sarah Kim(Broad Institute), Peter P. Du(Broad Institute), Arvin Iracheta‐Vellve(Broad Institute), Emily Robitschek(Broad Institute), Juliette S. M. T. Suermondt(Broad Institute), Thomas Davis(Broad Institute), Clara Wolfe(Broad Institute), Trisha Atluri(Broad Institute), Kira E. Olander(Broad Institute), Jason S. Rush(Broad Institute), Thomas B. Sundberg(Broad Institute), Fiona E. McAllister(Enzo Life Sciences (United States)), Jennifer G. Abelin(Broad Institute), Ari J. Firestone(Enzo Life Sciences (United States)), David Stokoe(Enzo Life Sciences (United States)), Steven A. Carr(Broad Institute), Fiona Harding(ISCO International (United States)), Kathleen B. Yates(Broad Institute), Robert T. Manguso(Broad Institute)
Cited by 20Open Access
Abstract
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.
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