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  3. Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype

Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype

  • Cancer Discov. 2025 Jun 18:OF1-OF16. doi: 10.1158/2159-8290.CD-24-1208.
Joanna Pozniak # 1 2,  Niccolò Roda # 1 2,  Ewout Landeloos # 1 2 3,  Asier Antoranz 4,  Yannick Van Herck 3,  Amber De Visscher 5,  Philip Georg Demaerel 1 2 6,  Lukas Vanwynsberghe 1 2,  Jeroen Declercq 1 2,  Christos Gkemisis 1 2,  Greet Bervoets 1 2,  No-Joon Song 7,  Ayse Bassez 8 9,  Robin Browaeys 10 11,  Lotte Pollaris 10 11,  Francesca M Bosisio 12,  Veerle Boecxstaens 13,  Yvan Saeys 10 11,  Diether Lambrechts 8 9,  Zihai Li 7 14,  Patrick Matthys 5,  Oliver Bechter 3,  Jean-Christophe Marine 1 2
Affiliations

Affiliations

  • 1 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 2 Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 3 Department of General Medical Oncology, UZ Leuven, Leuven, Belgium.
  • 4 Laboratory of Translational Cell and Tissue Research, Department of Pathology, KU Leuven, Leuven, Belgium.
  • 5 Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
  • 6 Department of Dermatology, UZ Leuven, Leuven, Belgium.
  • 7 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center- James Cancer Center and Solove Research Institute, Columbus, Ohio.
  • 8 Laboratory of Translational Genetics, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 9 Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • 10 Data Mining and Modelling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium.
  • 11 Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium.
  • 12 Department of Pathology, UZLeuven, Leuven, Belgium.
  • 13 Department of Surgical Oncology, UZLeuven, Leuven, Belgium.
  • 14 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • # Contributed equally.
PMID: 40530504 DOI: 10.1158/2159-8290.CD-24-1208
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 article by Song et al., p. XX.

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