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Updated: Jul 28, 2026
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
Bérengère Salomé1, John P Sfakianos2, Daniel Ranti3
1The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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.
Insights
NKG2A blockade enhances immunotherapy for bladder cancer by improving CD8+ T cell responses, particularly in tumors with low HLA-ABC expression. This approach targets T cell receptor-independent mechanisms for better survival outcomes.
Area of Science:
- Immunology
- Oncology
- Cancer immunotherapy
Background:
- PD-1/PD-L1 blockade shows limited efficacy in bladder cancer treatment.
- NKG2A expression on CD8+ T cells correlates with improved survival and immunotherapy response.
- NKG2A is acquired later than PD-1 on CD8+ T cells in bladder tumors.
Purpose of the Study:
- To investigate the role of NKG2A in bladder cancer immunity.
- To explore NKG2A+ CD8+ T cells' unique anti-tumor mechanisms.
- To evaluate NKG2A blockade as a potential immunotherapy strategy.
Main Methods:
- Analysis of NKG2A and PD-1 expression on CD8+ T cells in bladder tumors.
- Characterization of NKG2A+ PD-1+ CD8+ T cells' response to HLA class I-deficient tumors.
- Assessment of NKG2A+ CD8+ T cell function in tumors expressing HLA-E.
- Evaluation of NKG2A blockade efficacy in an HLA-E-dependent manner.
Main Results:
- NKG2A+ PD-1+ CD8+ T cells exhibit TCR-independent anti-tumor activity against HLA-deficient tumors.
- Tumor HLA-ABC expression decreases with disease progression.
- NKG2A+ CD8+ T cells are inhibited by tumor HLA-E expression.
- NKG2A blockade partially restores NKG2A+ CD8+ T cell function in an HLA-E-dependent manner.
Conclusions:
- NKG2A+ CD8+ T cells represent a distinct T cell subset with innate-like anti-tumor functions.
- Targeting NKG2A offers a promising strategy to enhance bladder cancer immunotherapy, especially in tumors with diminished HLA expression.
- Combining NKG2A blockade with other immunotherapies may improve outcomes for bladder cancer patients.
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