1. Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint.
- Author
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Tsao HW, Anderson S, Finn KJ, Perera JJ, Pass LF, Schneider EM, Jiang A, Fetterman R, Chuong CL, Kozuma K, Stickler MM, Creixell M, Klaeger S, Phulphagar KM, Rachimi S, Verzani EK, Olsson N, Dubrot J, Pech MF, Silkworth W, Lane-Reticker SK, Allen PM, Ibrahim K, Knudsen NH, Cheng AY, Long AH, Ebrahimi-Nik H, Kim SY, Du PP, Iracheta-Vellve A, Robitschek EJ, Suermondt JSMT, Davis TGR, Wolfe CH, Atluri T, Olander KE, Rush JS, Sundberg TB, McAllister FE, Abelin JG, Firestone A, Stokoe D, Carr SA, Harding FA, Yates KB, and Manguso RT
- Subjects
- Animals, Mice, Humans, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Neoplasms immunology, Immune Checkpoint Inhibitors pharmacology, Antigen Presentation immunology, Mice, Knockout, Mice, Inbred C57BL, Aminopeptidases metabolism, Aminopeptidases genetics, NK Cell Lectin-Like Receptor Subfamily C metabolism, NK Cell Lectin-Like Receptor Subfamily C immunology, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class I metabolism, Minor Histocompatibility Antigens metabolism, Minor Histocompatibility Antigens genetics, HLA-E Antigens
- 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., Competing Interests: 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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