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. 2024 Dec 10;57(12):2863-2878.e12.
doi: 10.1016/j.immuni.2024.10.013. Epub 2024 Nov 18.

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

Hsiao-Wei Tsao  1 , Seth Anderson  1 , Kenneth J Finn  2 , Jonathan J Perera  1 , Lomax F Pass  1 , Emily M Schneider  1 , Aiping Jiang  1 , Rachel Fetterman  1 , Cun Lan Chuong  1 , Kaiya Kozuma  1 , Marcia M Stickler  2 , Marc Creixell  2 , Susan Klaeger  3 , Kshiti Meera Phulphagar  3 , Suzanna Rachimi  3 , Eva K Verzani  3 , Niclas Olsson  2 , Juan Dubrot  1 , Matthew F Pech  2 , Whitney Silkworth  2 , Sarah Kate Lane-Reticker  1 , Peter M Allen  1 , Kyrellos Ibrahim  1 , Nelson H Knudsen  1 , Andrew Y Cheng  1 , Adrienne H Long  4 , Hakimeh Ebrahimi-Nik  1 , Sarah Y Kim  1 , Peter P Du  1 , Arvin Iracheta-Vellve  1 , Emily J Robitschek  1 , Juliette S M T Suermondt  1 , Thomas G R Davis  1 , Clara H Wolfe  1 , Trisha Atluri  1 , Kira E Olander  1 , Jason S Rush  3 , Thomas B Sundberg  3 , Fiona E McAllister  2 , Jennifer G Abelin  3 , Ari Firestone  2 , David Stokoe  2 , Steven A Carr  3 , Fiona A Harding  5 , Kathleen B Yates  6 , Robert T Manguso  7
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Free article

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

Hsiao-Wei Tsao et al. Immunity. .
Free article

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.

Keywords: ERAP; HLA-E; NKG2A; Qa-1b; Qdm; VL9; antigen presentation; checkpoint blockade; immunotherapy; peptide loading complex.

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Conflict of interest statement

Declaration of interests This manuscript is the result of a collaborative effort between the Broad Institute and Calico Life Sciences, LLC and was supported by funding from Calico Life Sciences, LLC. K.J.F., M.M.S., M.C., N.O., F.E.M., A.F., D.S., and F.A.H. are current employees of Calico Life Science, LLC. S.K. was an employee of Broad Institute at the time she contributed to the work and is a current employee of Genentech. M.F.P. was an employee of Calico Life Sciences at the time he contributed to the work and is a current employee of TenSixteen Bio. W.S. was an employee of Calico Life Sciences at the time she contributed to the work. A.I.-V. was an employee of the Broad Institute at the time he contributed to the work and is a current employee of Monte Rosa Therapeutics. T.G.R.D. was an employee of the Broad Institute at the time he contributed to the work and is a current employee of Tessera Therapeutics. T.A. was an employee of the Broad Institute at the time she contributed to the work and is a current employee of ZS. T.B.S. was an employee of the Broad Institute at the time he contributed to the work and is a current employee of Johnson & Johnson Innovative Medicine. R.T.M. has received speaking or consulting fees from Bristol Myers Squibb, Gilead Sciences, Kumquat Biosciences, and Immunai Therapeutics and has equity ownership in OncoRev, LLC. Calico Life Sciences, LLC and the Broad Institute participated in the interpretation of data, review, and approval of the publication.

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