Tumor-Experienced Human NK Cells Express High Levels of PD-L1 and Inhibit CD8⁺ T Cell Proliferation

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Natural Killer (NK) cells are crucial for cancer immunosurveillance.
• NK cells in cancer patients often show impaired functions and altered phenotypes.
• Emerging evidence suggests NK cells have regulatory roles in various immune conditions.

Purpose of the Study:

• To investigate the role of NK cells in clear cell renal cell carcinoma (ccRCC).
• To analyze the phenotype and function of tumor-infiltrating NK cells in ccRCC patients.
• To explore the potential immunoregulatory functions of PD-L1 expressing NK cells in ccRCC.

Main Methods:

• Analysis of ccRCC datasets from The Cancer Genome Atlas (TCGA).
• Characterization of tumor-infiltrating NK cells from fresh ccRCC patient samples.
• In vitro studies involving NK cell activation, PD-L1 induction, and co-culture with CD8+ T cells.

Main Results:

• Higher NK cell gene expression correlated with reduced survival in ccRCC patients.
• A high frequency of PD-L1-positive (PD-L1+) NK cells was found in ccRCC tumors.
• In vitro, PD-L1+ NK cells exhibited enhanced effector functions but inhibited CD8+ T cell proliferation in a PD-L1-dependent manner.

Conclusions:

• Tumors may induce PD-L1 expression on NK cells, leading to acquired immunoregulatory functions in humans.
• PD-L1+ NK cells in ccRCC can suppress anti-tumor CD8+ T cell responses.
• Targeting these regulatory NK cells presents a potential strategy to enhance anti-cancer immunity.