Natural Killers at the Neuro-Immune Axis!

Much has been said about the role Natural Killer (NK) cells play in positively and negatively influencing events in tissues and cells. Summarized facts about the healthy state of NK cells in humans and animals explain how innate immune cells, including NK cells differ from adaptive immune cells. One significant feature of NK cells is that they can act independently of MHC antigen presentations and that makes them tantalizing, but enormously challenging for scientists seeking to embrace their  influence over cells and their killing capabilities.

The variety and combination of inhibitory and activating receptors differentially expressed by as many as 30,000 human NK cell subsets makes heterogeneity difficult to relate across different conditions, organs and tissue types. Notwithstanding, positive rates of overall patient survival resoundingly corelated to the presence of as few as one NK cell infiltrating a tumor in a microscopic field.  

Innate immune cells including NK and macrophages have also been directly tied to conditions of neurological pain and more specifically to afferent and efferent fibers that signal through the vagus nerve. In these models at the immune-neurological interface similarities exists and both organs must interact for proper function. 

In each of these organs communication is mediated by direct cellular contact eg. synapse formation and via soluble mediators like cytokines or neurotransmitters that also communicate bi-directionally between cells of each system. The nervous and immune systems can influence each other’s activity because immune cells express neurotransmitter receptors, and neurons express cytokine receptors. Immune cells can synthesize and release neurotransmitters themselves, thus using neurotransmitter-mediated pathways via autocrine and paracrine mechanisms. This may indicate that NK cells extend nerve end signaling further into tissues and at a cellular level. 

A recent paradigm in physiology describes the existence of neuro-immune cell units, at an organ-tissue level and identifies the enormous complexity inherent in this globally unifying approach that also connects neuro-immune-gut, at least in Parkinson's disease.

Parkinson’s is a brain disorder where certain nerve cells slowly die and symptoms worsen. The risk of developing the condition increases with age, but in certain patients the illness is caused by defects in two proteins, PINK1 and parkin. NK cells are capable of homing to the central nervous system in neurological disorders that exhibit exacerbated inflammation and inhibit hyperactivated microglia. Recently, a study demonstrated that NK cells scavenge alpha-synuclein aggregates and systemic depletion of NK cells results in exacerbated neuropathology in a mouse model of alpha-synucleinopathy, making NK cells highly relevant in Parkinson’s disease.

We recently described a mechanism by which the sentinel state of NK cells is impaired and suggested the senescent phenotype, induced by age related mitophagy could be the primary cause. Increase in mitophagy (mitochondrial autophagy) is age-dependent and abrogated by PINK1 or parkin deficiency suggesting, in Parkinson's disease compromised mitophagy is associated with neurological degeneration. Further  PINK1 and Parkin, which are regulated by p53 specifically repress mitochondrial antigen presentation of both MHC classes. Therefore, excessive PINK1 or parkin increases rates of NK cell mitophagy and repress the presentation of mitochondrial antigens for MHC classes at the axis of this neuro-immune related disease.

The healthy state of NK cells at the axis of neuro-immune systems may indeed have more far reaching implications for the future of human diseases and therapies.

 

Natural Killers Linked to Overall Survival in Cancer

A meta analysis of tumor samples, collected between 1973 and 2016, in 53 studies confirmed overall survival (OS) correlated with Natural Killer cell infiltration into solid tumors. The number of NK cells infiltrating solid tumors, including those considered “highly ”infiltrated was relatively low, compared with other immune populations. Notwithstanding, the presence of a single NK cell, within a high powered microscopic field was associated with significantly improved OS and disease free survival in colorectal cancer, HER2 + breast cancer and hepatocellular carcinoma.

The finding supports the prospect that single tumor infiltrating NK cells, in a sampled tissue can be determinative for OS. By inference a single tumor infiltrating NK cell or cells possess characteristics that are relative to OS and beneficial to patient.  

NK cell surface receptors are densely varied defining at least 30,000 unique NK cell populations within each individual. NK cell classifications, relative to tumor infiltration and OS is enormously complex, especially at this scale and present definitions of activating and inhibiting receptor combinations underwhelm. To identify NK cells that have infiltrated or may be capable of infiltrating a patient tumor to improve OS we focused on biopsied tumor tissue selections whether or not they include NK cells.

Our work is with two tumor types in humanized mice. Multiple sections of each tumor were resected and divided into multiple parts for coculture with allogenic naïve, IL2 and probiotic enhanced NK cells and for DNA sequencing. After coculture NK cell cytotoxicity and other detailed measures resulting from each resected section and from single cells were assessed. Presently sequencing of DNA from each resected, divided section (pre-coculture) is focused on comparisons derived from TP53.

In the final stage NK cells will be cocultured with resected tumor tissue and will be made to challenge new tumor tissue and single cells, from the resected tumor from which the NK coculture was derived. The objective will be whether Codondex analysis of TP53 DNA sequencing can predict the most successful tumor tissue candidates based upon the most effective cocultured NK cell challenge to the tumor derived tissue or cells. 

If Codondex algorithm is found to identify a direct or indirect logic for tissue or cell selection that is effective in vitro our work will continue to next stage in vivo testing and analysis on similar grounds.