Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype
Year: 2025
Type: article
Abstract: Immune checkpoint blockade (ICB) has revolutionized cancer treatment. Unfortunately, the inability of lymphocytes to infiltrate the tumor nest, a phenomenon known as immune exclusion, drastically limits ICB responsiveness. Analyzing the immune landscape of matched pre- and early on-treatment biopsies of patients with melanoma undergoing ICB therapy, we observed a significant increase in cytotoxic NK cells in early on-treatment biopsies from nonresponders. Spatial multiomic analyses revealed that, although NK cells colocalized with CD8+ T cells within the tumor bed in responding lesions, they were excluded from the tumor parenchyma in nonresponding lesions. Strikingly, pharmacologic depletion of NK cells in a unique melanoma mouse model exhibiting an immune-excluded phenotype unleashed immune infiltration of the tumor core and tumor clearance upon ICB exposure. Mechanistically, we show that NK cells are actively recruited to immune-excluded areas upon ICB exposure via the chemokine receptor CX3CR1 to suppress tumor infiltration and antitumor function of CD8+ T cells. SIGNIFICANCE: Immune exclusion is responsible for intrinsic resistance to ICB in about half of nonresponder patients. Our unexpected observation that targeting NK cell biology unleashes the recruitment and antitumor activity of CD8+ T cells in tumors with an immune-excluded phenotype offers a potential therapeutic avenue for this large patient population. See related commentary by Galvez-Cancino et al., p. 1777 See related article by Song et al., p. 1835.
Source: Cancer Discovery
Authors: Joanna Pozniak, Niccolò Roda, Ewout Landeloos, Asier Antoranz, Yannick Van Herck, Amber De Visscher, Philip Georg Demaerel, Lukas Vanwynsberghe, Jeroen Declercq, Christos Gkemisis, Greet Bervoets, No-Joon Song, Ayse Bassez, Robin Browaeys, Lotte Pollaris, Francesca M. Bosisio, Veerle Boecxstaens, Yvan Saeys, Diether Lambrechts, Zihai Li, Patrick Matthys, Oliver Bechter, Jean-Christophe Marine
Institutions: VIB-KU Leuven Center for Cancer Biology, KU Leuven, Universitair Ziekenhuis Leuven, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Ghent University, VIB-UGent Center for Inflammation Research, The Ohio State University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1703054418, G2837392198, G3234278102, G3399927686, G3589910354, G6037444302, Exploring the pathogenesis of Macrophage Activation Syndrome by studying a type 1 Innate Lymphoid Cell population in mouse models and in patients, Interpretable models for integrative single-cell spatial transcriptomics, G6995935210, G7211173021, Mapping the multi-modal single-cell landscape of metastatic and non-metastatic thin melanoma.
OpenAlex ID: W4411426774