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

IF 16.4 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2026-06-05 DOI:10.1126/sciimmunol.aeb6645

Clara Serger, Lucas Rebuffet, Michael T. Sandholzer, Wiebke Rackwitz, Irene Fusi, Petra Herzig, Annalea Brüggemann, Carina A. Pawlow, Evgeny Chichelnitskiy, Daniel Hajnal, Nicole Oelgarth, Sarp Uzun, Christoph Schultheiß, Andreas Zingg, Sofia Tundo, Thuy T. Luu, Aljaz Hojski, Didier Lardinois, Lavinia Neubert, Mascha Binder, Kirsten Mertz, Marcel P. Trefny, Nicole Kirchhammer, Marina Natoli, Matthias S. Matter, Heinz Läubli, Christine Falk, Karin Schaeuble, Eric Vivier, Andrea Romagnani, Alfred Zippelius

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Abstract

Natural killer (NK) cell–targeting immunotherapies are emerging, yet the differentiation and functional states of tumor-infiltrating NK cells remain poorly understood. Using matched single-nucleus RNA and ATAC sequencing of samples from patients with non–small cell lung cancer (NSCLC), we resolved the transcriptional and epigenetic landscape of intratumoral NK cells. We identified two tumor-associated NK (taNK) cell subsets marked by expression of ITGAE (CD103) and ITGA1 (CD49a) that display features of tissue residency and dysfunction while preserving cytotoxic function. Trajectory and regulon analyses revealed an inflammation-driven transition from early granzyme K (GZMK)⁺ NK cells toward an ENTPD1⁺ (CD39⁺) effector state characterized by interferon-stimulated gene (ISG) programs. Functional profiling established CD39⁺ taNK cells as the dominant cytotoxic NK cell population with superior killing capacity that was further potentiated by NKG2A blockade. This study offers mechanistic insights into NK cell differentiation in NSCLC and establishes CD39⁺ taNK cells as a targetable effector population for immunotherapy.

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肺癌中细胞毒性CD39+肿瘤相关NK细胞对NKG2A阻断有反应

自然杀伤（NK）细胞靶向免疫疗法正在兴起，但肿瘤浸润NK细胞的分化和功能状态仍然知之甚少。利用非小细胞肺癌（NSCLC）患者样本的匹配单核RNA和ATAC测序，我们解决了肿瘤内NK细胞的转录和表观遗传学景观。我们发现了两个肿瘤相关的NK （taNK）细胞亚群，以ITGAE （CD103）和ITGA1 （CD49a）的表达为标志，它们在保留细胞毒性功能的同时表现出组织驻留和功能障碍的特征。轨迹和调控分析揭示了炎症驱动的从早期颗粒酶K (GZMK)+ NK细胞向干扰素刺激基因（ISG）程序表征的ENTPD1+ (CD39+)效应状态的转变。功能分析证实CD39+ taNK细胞是主要的细胞毒性NK细胞群，具有优越的杀伤能力，NKG2A阻断进一步增强了杀伤能力。本研究提供了NK细胞在NSCLC中分化的机制，并建立了CD39+ taNK细胞作为免疫治疗的靶效应群体。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.