A natural killer cell gene signature predicts melanoma patient survival

Abstract

Animal models have demonstrated that natural killer (NK) cells can limit the metastatic dissemination of tumors, however their ability to combat established human tumors has been difficult to investigate.A number of computational methods have been developed for the deconvolution of immune cell types within solid tumors. We have taken the NK cell gene signatures from several tools, then curated and expanded this list using recent reports from the literature. Using a gene set scoring method to investigate RNA-seq data from The Cancer Genome Atlas (TCGA) we show that patients with metastatic cutaneous melanoma have an improved survival rate if their tumor shows evidence of greater NK cell infiltration. Furthermore, these survival effects are enhanced in tumors which have a higher expression of NK cell stimuli such as IL-15, suggesting NK cells are part of a coordinated immune response within these patients. Using this signature we then examine transcriptomic data to identify tumor and stromal components which may influence the penetrance of NK cells into solid tumors.These data support a role for NK cells in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. Furthermore, our computational analysis identifies a number of potential targets which may help to unleash the anti-tumor potential of NK cells as we enter the age of immunotherapy. Developmentof methodology: J. Cursons, M. Foroutan, M.J. Davis Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions

“…Despite their discovery in the early 1970s as “killer cells with rapid cytolytic, specific activity” toward murine leukemia cells, exploiting NK cells in human disease has remained elusive due to limited understanding of the mechanisms regulating their function. Growing evidence for the role of NK cells in cancer immune surveillance and clearance has included human data demonstrating that patients with high intratumoral NK cell frequency have significantly improved survival outcomes . Thus, it is not surprising that NK cells have become a high priority in immunotherapy development …”

“…Growing evidence for the role of NK cells in cancer immune surveillance and clearance has included human data demonstrating that patients with high intratumoral NK cell frequency have significantly improved survival outcomes. 2 Thus, it is not surprising that NK cells have become a high priority in immunotherapy development. [3][4][5] Clinical investigation of NK cells for the treatment of malignancies has followed similar rationale to the work horses of immunotherapy: CD8 + T cells; hence, clinical applications have been comparable.…”

The HIV latency reversal agent HODHBt enhances NK Cell effector and memory-like functions by increasing IL-15 mediated-STAT activation

“…The copyright holder for this preprint this version posted October 14, 2021. ; https://doi.org/10.1101/2021.10.14.464348 doi: bioRxiv preprint the last decade [65][66][67][68][69][70]. NK cells are an alternative to T cell immunotherapies because they preferentially target transformed cells, without the need for prior sensitization or known antigens.…”

“…the last decade [65][66][67][68][69][70]. NK cells are an alternative to T cell immunotherapies because they preferentially target transformed cells, without the need for prior sensitization or known antigens.…”

Strategies for improving T-cell manufacturing for adoptive immunotherapies

“…Unlike T-cells, NK cells are part of the innate immune system and therefore are not dependent on antigen presentation for anti-tumour function [285,286]. A number of studies have highlighted the anti-tumour functions and clinical utility of NK cells [287][288][289]. Indeed, adoptive transfer of allogeneic NK cells has demonstrated safety and efficacy for this immunotherapy approach [290,291].…”