NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
Cancer Cell(2022)
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(+) T cells. In bladder tumors, NKG2A is acquired on CD8(+) T cells later than PD-1 as well as other well -established immune checkpoints. NKG2A(+) PD-1+ CD8(+) 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(+) CD8(+ )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.
MoreTranslated text
Key words
CD8 T cells,NK cells,immune exhaustion,solid tumors,tumor microenvironment,HLA class I,NKG2A,bladder cancer,checkpoint blockade immunotherapy
AI Read Science
Must-Reading Tree
Example
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined