ORIGINAL RESEARCH article
Front. Immunol.
Sec. NK and Innate Lymphoid Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1646849
Comparative Transcriptomic Analysis of Tumor-Infiltrating Canine Natural Killer (NK) Cells and Candidate Biomarkers from First-in-Dog NK Immunotherapy Trials
Provisionally accepted- 1Department of Surgery, University of California Davis School of Medicine, Sacramento, United States
- 2Department of Dermatology, University of California Davis School of Medicine, Sacramento, United States
- 3Department of Surgical and Radiological Sciences, University of California Davis School of Veterinary Medicine, Davis, United States
- 4Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, United States
- 5Department Population Health and Reproduction, University of California Davis School of Veterinary Medicine, Davis, United States
- 6Department of Medical Sciences, University of Wisconsin-Madison School of Veterinary Medicine, Madison, United States
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Natural killer (NK) cells have great potential to extend the promise of cancer immunotherapy, but additional research is needed to improve their efficacy in solid cancers. Dogs develop spontaneous cancers with striking similarities to humans and can serve as a crucial link to bridge murine studies and human clinical trials to improve treatment outcomes across species and identify potential biomarkers of response. Using single-cell RNA sequencing (scRNAseq), we integrated blood, tissue, and tumor samples from dog and human donors to compare NK cell gene expression and develop a canine sarcoma infiltrating NK signature. Canine tissue and tumor NK cell signatures were then used to contextualize NK cell changes in first-in-dog immunotherapy clinical trials. Tumor infiltrating NK cells from both canine and human sarcomas exhibited enhanced migration with a simultaneously exhausted signature that most closely correlated transcriptionally with NK cells isolated from the liver. We also analyzed peripheral blood NK cells from dogs on first-in-dog clinical trials undergoing three distinct NK-targeting immunotherapy regimens, observing that dogs with favorable responses demonstrated increased NK proportions post-treatment. Genes upregulated in NK cells in the peripheral blood of good responders included genes associated with activated NK cells and revealed post-treatment gene expression changes in the blood as a predictor of response. Overall, NK effector functions are well adapted to their tissue of residence but dysregulated in sarcoma infiltrating NK cells despite enhanced migration. We describe NK cell trends across canine clinical trials as a platform through which we can elucidate mechanisms of response and determine novel immunotherapy strategies to improve cancer outcomes in both humans and dogs.
Keywords: natural killer (NK) cells, cancer immunotherapy, Single-cell RNA sequencing (scRNAseq), canine sarcoma infiltrating NK signature, Tumor infiltrating NK cells, canine and human sarcomas, NK-targeting immunotherapy regimens, NK activation genes
Received: 14 Jun 2025; Accepted: 03 Oct 2025.
Copyright: © 2025 Razmara, Lammers, Judge, Sholevar, Murphy, Gaskill, Culp, Gingrich, Morris, Rebhun, Brown, Vail, Kent and Canter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Robert J. Canter, rjcanter@health.ucdavis.edu
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