Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer
(1) Serger C (2) Rebuffet L (3) Sandholzer MT (4) Rackwitz W (5) Fusi I (6) Herzig P (7) Brggemann A (8) Pawlow CA (9) Chichelnitskiy E (10) Hajnal D (11) Oelgarth N (12) Uzun S (13) Schulthei§ C (14) Zingg A (15) Tundo S (16) Luu TT (17) Hojski A (18) Lardinois D (19) Neubert L (20) Binder M (21) Mertz K (22) Trefny MP (23) Kirchhammer N (24) Natoli M (25) Matter MS (26) Lubli H (27) Falk C (28) Schaeuble K (29) Vivier E (30) Romagnani A (31) Zippelius A
Serger et al. profiled NK cells in NSCLC, and identified two tumor-associated NK cell (taNK; CD103+CD49a+) populations. These cells were cytotoxic, but showed hallmarks of dysfunction. Trajectory analysis showed a transition from the CD56bright phenotype through an interferon response and GZMB induction, leading to the expression of genes related to tissue residency, dysfunction, and cytotoxicity. The CD39-expressing subset of taNK cells had the highest tumor killing capacity and responded to anti-NKG2A therapy.
(1) Serger C (2) Rebuffet L (3) Sandholzer MT (4) Rackwitz W (5) Fusi I (6) Herzig P (7) Brggemann A (8) Pawlow CA (9) Chichelnitskiy E (10) Hajnal D (11) Oelgarth N (12) Uzun S (13) Schulthei§ C (14) Zingg A (15) Tundo S (16) Luu TT (17) Hojski A (18) Lardinois D (19) Neubert L (20) Binder M (21) Mertz K (22) Trefny MP (23) Kirchhammer N (24) Natoli M (25) Matter MS (26) Lubli H (27) Falk C (28) Schaeuble K (29) Vivier E (30) Romagnani A (31) Zippelius A
Serger et al. profiled NK cells in NSCLC, and identified two tumor-associated NK cell (taNK; CD103+CD49a+) populations. These cells were cytotoxic, but showed hallmarks of dysfunction. Trajectory analysis showed a transition from the CD56bright phenotype through an interferon response and GZMB induction, leading to the expression of genes related to tissue residency, dysfunction, and cytotoxicity. The CD39-expressing subset of taNK cells had the highest tumor killing capacity and responded to anti-NKG2A therapy.
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.
Author Info:
(1) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (2) Aix Marseille Universit, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy
, Marseille, France. (3) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (4) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (5) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (6) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (7) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (8) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (9) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. (10) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (11) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (12) Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland. (13) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (14) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (15) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Roche Pharma Research and Early Development pRED, Roche Innovation Center, Basel, Switzerland. (16) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (17) Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland. (18) Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland. (19) German Centre for Lung Diseases (DZL), BREATH site, Hannover, Germany. Institute of Pathology, Hannover Medical School, Hannover, Germany. (20) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Medical Oncology, University Hospital Basel, Basel, Switzerland. (21) Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland. (22) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (23) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (24) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (25) Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland. (26) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Medical Oncology, University Hospital Basel, Basel, Switzerland. (27) Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany. German Centre for Lung Diseases (DZL), BREATH site, Hannover, Germany. German Centre for Infection Research (DZIF), TTU-IICH, Hannover/Braunschweig site, Hannover, Germany. (28) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. (29) Aix Marseille Universit, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France. APHM, Hpital de la Timone, Marseille-Immunople Profiling Platform, Marseille, France. Paris-Saclay Cancer Cluster, Villejuif, France. Ecole Polytechnique, Palaiseau, France. (30) Roche Pharma Research and Early Development pRED, Roche Innovation Center, Basel, Switzerland. (31) Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland. Medical Oncology, University Hospital Basel, Basel, Switzerland.
Citation: Sci Immunol 2026 Jun 5 11:eaeb6645 Epub06/05/2026
