Tissue-resident Natural Killer cells in human lung cancer

Background: Natural killer (NK) cells, part of the innate lymphoid cell family, represent the third major lymphocytic population in the peripheral blood and are traditionally divided into CD56dimCD16+ and CD56brightCD16− subsets. However, recent research has identified tissue-resident(tr) NK cells in different organs, such as lung and liver. These cells are distinguished by the circulating counterpart by expression of markers, such as CD103, CD69, CXCR6, and CD49a responsible for their retention in tissues. Our group and others have recently observed the presence of distinct subsets of tr-NK cells among total lymphocytic infiltrate of NSCLC. While the role of tr-NK cells in normal tissue homeostasis has been, at least in part, clarified, their function in tumor microenvironment (TME) remains poorly understood. Purpose: The main objective of this study was to investigate the function and ontogeny of tr-NK cells in TME of human NSCLC. We mainly focused on CD103+ tr-NK cells, because of their potential to interact with epithelial tumor cells through the recognition of E-cadherin. Results: We found that tumor-infiltrating CD103+ NK cell showed dysregulation in IFN-γ, TNF-α production and degranulation toward tumor targets, but maintained expression of chemotactic factors important for recruitment of Dendritic Cells. Interestingly, their functional abilities can be partially restored in the presence of activating cytokines like IL-15. Regarding the potential origin of CD103+ NK cells in tumor, by using a 3D spheroid model of NSCLC, we also observed that only circulating CD56bright NK cells, but not the CD56dim counterpart, could efficiently infiltrate tumor masses. Interestingly, CD56bright infiltrating spheroids acquired CD103 and other features of NK cell counterpart present in the TME. Conclusions: Our data suggests that steady-state tumor-infiltrating CD103+ NK cells show limited pro-inflammatory function despite maintaining expression of chemotactic factors able to recruit other immune effectors. However, these limitations might be overcome by stimulating cytokines. Moreover, our data emphasizes a unique capability for CD56bright NK cell in infiltrating tumor mass and convert to CD103+ tr-NK cells. Overall, these results prompt us to investigate further strategies to stimulate endogenous NK cells to boost antitumor immunity.