PXD052031

PXD052031 is an original dataset announced via ProteomeXchange.

Title	Targeting ERAP enhances anti-tumor immunity by disrupting the NKG2A/HLA-E inhibitory checkpoint
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-11-21
AnnouncementXML	Submission_2024-11-21_09:31:37.329.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Niclas Olsson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-06 17:07:24	ID requested
⏵ 1	2024-11-21 09:31:38	announced

10.1016/j.immuni.2024.10.013;

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, Manguso RT, Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint. Immunity, 57(12):2863-2878.e12(2024) [pubmed]

submitter keyword: Human, HLA-E, Orbitrap, Immunotherapy

Fiona McAllister
contact affiliation	Calico Life Sciences
contact email	fiona@calicolabs.com
lab head
Niclas Olsson
contact affiliation	Calico Life Sciences
contact email	niclas@calicolabs.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD052031
     1. Label: PRIDE project
     2. Name: Targeting ERAP enhances anti-tumor immunity by disrupting the NKG2A/HLA-E inhibitory checkpoint