MassIVE MSV000094736

Partial Public PXD052175

Targeting ERAP enhances anti-tumor immunity by disrupting the NKG2A/HLA-E inhibitory checkpoint

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Description

Tsao H, Anderson S, Finn KJ, Perera J, 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, Manguso RT. 2024 New targets that enhance anti-tumor immunity must be identified to improve the efficacy of cancer immunotherapy. Here we show that loss of endoplasmic reticulum aminopeptidase (ERAP) family proteins improves anti-tumor immunity and synergizes with immune checkpoint blockade. Mechanistically, we show that loss of ERAP inactivates the HLA-E/NKG2A checkpoint, which normally restrains tumor killing by both CD8+ T cells and NK cells. The inhibitory activity of HLA-E is dependent on its presentation of a restricted set of invariant epitopes which form the binding surface for the NKG2A/CD94 receptor complex. Using genetic screening, in vivo models, cell-based assays, and immunopeptidomics, we show that loss of ERAP activity prevents the processing of these invariant peptides and alters the presented peptidome of both HLA-E and classical MHC-I. HLA-E neo-peptides presented after ERAP deletion are unable to bind the NKG2A/CD94 receptor, rendering tumor cells highly susceptible to killing by NKG2A+ cytotoxic T and NK cells. Thus, loss of ERAP phenocopies the loss or inhibition of the HLA-E/NKG2A pathway and represents an attractive therapeutic approach to inhibit this critical checkpoint. More broadly, this work identifies ERAP1/2 as druggable intracellular enzymes that could be targeted using small molecules to inactivate a cell-surface inhibitory pathway and represents a novel approach to therapeutic modulation of immune responses. [doi:10.25345/C59P2WH89] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: ERAP ; TMT11 ; immunopeptidomics ; HLA-I

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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