Discovery of Specialized NK Cell Populations Infiltrating Human Melanoma Metastases

NK cells contribute to protective anti-tumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis identified major differences in the transcriptional programs of tumor-infiltrating compared to circulating NK cells. Tumor-infiltrating NK cells represented seven clusters with distinct gene expression programs indicative of significant functional specialization, including cytotoxicity and chemokine synthesis programs. In particular, NK cells from three clusters expressed high levels of XCL1 and XCL2, which encode two chemokines known to recruit XCR1+ cross-presenting dendritic cells into tumors. In contrast, NK cells from two other clusters showed a higher level of expression of cytotoxicity genes. These data reveal key features of NK cells in human tumors and identify NK cell populations with specialized gene expression programs. Matching samples were collected from blood and tumor-infiltrating NK cells in 5 patients with melanoma metastasis.