Tissue resident lung natural killer (NK) cells demonstrate enhanced responses to IL-15 compared to peripheral populations

Abstract

Abstract Tissue resident NK cells with unique phenotype and function have been identified in organs such as the lung and liver. We have shown that inhaled (IH) rhIL-15 can lead to durable clinical responses in dogs with naturally occurring osteosarcoma or melanoma lung metastases, suggesting that lung NK populations can be targeted therapeutically. Thus, we set out to evaluate the phenotype of resting and rhIL-15-stimulated lung NK cells isolated from murine and human lung. C57BL/6 and BALB/c mice were exposed to IH or systemic IL-15 at escalating doses, and NK cells were isolated by negative selection from lungs and spleen of wild type mice for co-culture. In human patients undergoing surgery for malignancy, non-tumor lung tissue was isolated for flow cytometry and ex vivo stimulation with IL-15. Using mouse spleen or human blood as controls, we observed a higher proportion of lung NK cells per live CD45+ cells in baseline mouse and human samples. Lung NK also had higher expression of activation markers CD69 and HLA-DR (human), but lower expression of the inhibitory receptor TIGIT. Ex vivo culture with IL-15 also resulted in greater upregulation of Ki67 on lung NK cells. Compared to systemic delivery of IL-15, IH IL-15 resulted in greater upregulation of Ki67 and lower upregulation of TIGIT in lung NK cells. Subset analysis of CD49a+ lung NK cells showed similar results in both mouse and human models for activation marker and Ki67 expression after IL-15. Taken together, our results suggest that lung NK cells possess a more active baseline phenotype and exhibit preferential stimulation in response to rhIL-15 compared to circulating NK cells. Ultimately, targeting of lung resident NK cells may be a viable therapeutic strategy in patients with lung metastases. Supported by NIH/ NCI 1R03CA252793 NIH/NCI U01 CA224166-01 NIH/NCI T32 CA251007-01