Characterization and Potential Applications of Dog Natural Killer Cells in Cancer Immunotherapy

Abstract

Natural killer (NK) cells of the innate immune system are a key focus of research within the field of immuno-oncology based on their ability to recognize and eliminate malignant cells without prior sensitization or priming. However, barriers have arisen in the effective translation of NK cells to the clinic, in part because of critical species differences between mice and humans. Companion animals, especially dogs, are valuable species for overcoming many of these barriers, as dogs develop spontaneous tumors in the setting of an intact immune system, and the genetic and epigenetic factors that underlie oncogenesis appear to be similar between dogs and humans. Here, we summarize the current state of knowledge for dog NK cells, including cell surface marker phenotype, key NK genes and genetic regulation, similarities and differences of dog NK cells to other mammals, especially human and mouse, expression of canonical inhibitory and activating receptors, ex vivo expansion techniques, and current and future clinical applications. While dog NK cells are not as well described as those in humans and mice, the knowledge of the field is increasing and clinical applications in dogs can potentially advance the field of human NK biology and therapy. Better characterization is needed to truly understand the similarities and differences of dog NK cells with mouse and human. This will allow for the canine model to speed clinical translation of NK immunotherapy studies and overcome key barriers in the optimization of NK cancer immunotherapy, including trafficking, longevity, and maximal in vivo support.

A newly established canine NK‐type cell line and its cytotoxic properties

“…The established cell line expresses CD5, CD8, CD45, CD56, CD79a and NKp46 proteins and mRNA for NKG2D, NKp30, NKp44, NKp46 and perforin. NKp46 protein belongs to the group of activating receptors and is a particularly important molecule due to the fact that it was widely identified in the NK cells belonging to several mammalian species, including dogs 23 . Considering the fact that the canine natural killer cell population is still not precisely defined in the terms of phenotype, the positive signal from NKp46 is a valuable proof confirming NK cell properties of CNK‐89 cells.…”

Immunotherapy for Dogs: Still Running Behind Humans

“…Human NK cells express the characteristic CD56 antigen and are negative for CD3 expression. In contrast, NK cells from dogs are less well defined ( 17 ). Since their first description in 2000 ( 18 ), not much additional characteristics have been identified.…”

Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

“…The balance between these signals determines whether NK cells will activate their effector function (e.g., FasL/TRAIL-mediated killing, perforin/granzyme release, or cytokine production). In humans, there are several families of activating receptors, including CD126 (FcRγIIIa), natural cytotoxicity receptors (NCRs), NK Group 2 (NKG2) lectin-like receptors, DNAM-1, and 2B4; however, most of these have not been well-characterized in the dog ( 32 ). Activating receptors generally recognize proteins that are upregulated by cell stress or are of non-self-origin, whereas inhibitory receptors primarily bind MHC for self-recognition ( 33 ).…”