NKG2A inhibition promotes NK cell-CD8⁺ T cell interactions to improve anticancer immunity in ovarian carcinoma

Area of Science:

• Immunology
• Cancer Biology
• Cellular Immunology

Background:

• Natural killer (NK) cells are crucial for tumor immunosurveillance.
• NK cell heterogeneity and function across diverse cancer types are not fully understood.
• Dysfunctional NK cells expressing co-inhibitory receptors are observed in certain cancers.

Purpose of the Study:

• To investigate NK cell heterogeneity and function in non-small cell lung carcinoma (NSCLC) and high-grade serous ovarian carcinoma (HGSOC).
• To explore the functional interplay between NK cells and CD8+ T cells in antitumor immunity.
• To evaluate the therapeutic potential of targeting the NKG2A-HLA-E axis in HGSOC.

Main Methods:

• Transcriptomic, spatial, and functional assays were employed.
• Analysis of HGSOC patient samples and syngeneic mouse models.
• Assessment of NK cell and CD8+ T cell populations and their interactions.
• Evaluation of NKG2A blockade efficacy in combination with PD-1 blockade in preclinical models.

Main Results:

• NSCLC exhibits NK cells with potent effector functions, while HGSOC has dysfunctional NK cells expressing NKG2A.
• A critical crosstalk exists between NK cells and CD8+ T cells in HGSOC, essential for antitumor immunity.
• Depletion of either NK cells or CD8+ T cells impairs the other population.
• Blocking NKG2A restores NK cell cytotoxicity and enhances CD8+ T cell responses.
• NKG2A blockade significantly improves the efficacy of PD-1 blockade in murine HGSOC models.

Conclusions:

• NK cells and CD8+ T cells engage in a functionally relevant interplay within the tumor microenvironment.
• The NKG2A-HLA-E axis is a clinically actionable target in tumors characterized by impaired NK cell function.
• Targeting this axis offers a promising strategy to enhance cancer immunotherapy, particularly in HGSOC.