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.
Highlights
The innate immune system is comprised of a spectrum of innate lymphoid cells (ILC) that are capable of mounting an immune response to pathogens and “stressed” cells in the absence of major histocompatibility complex (MHC)-restricted receptor ligand interactions [1,2]
When killer-immunoglobulin-like receptors (KIRs) or Ly49 receptors are expressed and there is binding with MHC-I on target cells, natural killer (NK) cells do not initiate a cytotoxic response
For this reason, when MHC-I is downregulated, which often occurs in tumors and virally-infected cells as a strategy for evading antigen specific T cell responses, NK cells lose this inhibitory signal from inhibitory KIRs and Ly49s and the threshold for NK activation/ cytotoxicity is lower [6,10,11,16]
Summary
The innate immune system is comprised of a spectrum of innate lymphoid cells (ILC) that are capable of mounting an immune response to pathogens and “stressed” cells in the absence of major histocompatibility complex (MHC)-restricted receptor ligand interactions [1,2]. Recent work has elucidated further comparisons between cytotoxic T cells and NK cells with the discovery of induced NK cell memory or adaptive NK cells In these key studies, NK cells have demonstrated secondary responses, including recall towards specific antigen, such as (murine) cytomegalovirus (CMV/MCMV), human immunodeficiency virus (HIV), influenza viruses, and haptens [47,53,54]. NK cells have demonstrated secondary responses, including recall towards specific antigen, such as (murine) cytomegalovirus (CMV/MCMV), human immunodeficiency virus (HIV), influenza viruses, and haptens [47,53,54] Following such an exposure, Stage 6 NK cells appear to acquire an extended life span with the ability to self-renew in what was previously considered to be the stage of terminal differentiation [47,53,55,56]. Future studies on this topic will shed important insight into NK biology
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