Cytotoxic CD39⁺ tumor-associated NK cells respond to NKG2A blockade in lung cancer

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Natural killer (NK) cell immunotherapies are promising but require a deeper understanding of tumor-infiltrating NK cell states.
• The differentiation and function of NK cells within the tumor microenvironment of non-small cell lung cancer (NSCLC) are not well-characterized.

Purpose of the Study:

• To elucidate the transcriptional and epigenetic landscape of intratumoral NK cells in NSCLC.
• To identify and characterize distinct tumor-associated NK (taNK) cell subsets and their functional properties.

Main Methods:

• Matched single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) were performed on NSCLC patient samples.
• Trajectory and regulon analyses were employed to understand NK cell differentiation pathways.
• Functional profiling assessed the cytotoxic capacity of identified NK cell subsets.

Main Results:

• Two novel taNK cell subsets, marked by ITGAE (CD103) and ITGA1 (CD49a), were identified, exhibiting tissue residency and dysfunction with preserved cytotoxicity.
• An inflammation-driven transition was observed from early GZMK+ NK cells to an ENTPD1+ (CD39+) effector state, characterized by interferon-stimulated gene (ISG) programs.
• CD39+ taNK cells were confirmed as the predominant cytotoxic NK cell population with superior killing capacity, further enhanced by NKG2A blockade.

Conclusions:

• This study provides critical mechanistic insights into NK cell differentiation within the NSCLC tumor microenvironment.
• CD39+ taNK cells represent a highly effective, targetable effector population for advancing NSCLC immunotherapies.