NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.
Details
Serval ID
serval:BIB_2CBE768B4B2D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.
Journal
Cancer cell
ISSN
1878-3686 (Electronic)
ISSN-L
1535-6108
Publication state
Published
Issued date
12/09/2022
Peer-reviewed
Oui
Volume
40
Number
9
Pages
1027-1043.e9
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8 <sup>+</sup> T cells. In bladder tumors, NKG2A is acquired on CD8 <sup>+</sup> T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A <sup>+</sup> PD-1 <sup>+</sup> CD8 <sup>+</sup> T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A <sup>+</sup> CD8 <sup>+</sup> T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.
Keywords
B7-H1 Antigen/metabolism, CD8-Positive T-Lymphocytes, Histocompatibility Antigens Class I, Humans, NK Cell Lectin-Like Receptor Subfamily C/metabolism, Programmed Cell Death 1 Receptor, Urinary Bladder Neoplasms/therapy, CD8 T cells, HLA class I, NK cells, NKG2A, bladder cancer, checkpoint blockade immunotherapy, immune exhaustion, solid tumors, tumor microenvironment
Pubmed
Web of science
Create date
27/09/2022 12:49
Last modification date
11/03/2023 6:44