Tumor-Infiltrating NK Cells Exhibit Tumor Type–Specific Heterogeneity

Natural killer (NK) cells play a critical role in tumor control, but current NK cell–based therapies have not been effective in solid tumors, in part, due to a lack of understanding of tumor-infiltrating NK cell phenotypes and dysregulation. Tang, Li, and colleagues sought to elucidate the heterogeneity and dysfunction of NK cells at a pan-cancer level by constructing a comprehensive tumor-infiltrating human NK cell atlas using single-cell RNA sequencing data for 716 patients spanning 24 cancer types. NK cell composition was shown to be heterogeneous in a tumor type–specific manner, and widespread transcriptional alterations were also noted between tissue-infiltrating NK cells and those within the blood, with RGS1 being exclusively expressed by tissue-infiltrating NK cells across patients and cancer types, indicating its potential role as a marker for tissue-infiltrating NK cells. Moreover, a tumor-enriched NK cell population, termed tumor-associated NK (TaNK) cells, was identified and demonstrated the lowest cytotoxicity and highest stress scores. Data from The Cancer Genome Atlas indicated that high TaNK cell signals were associated with poor survival in most cancer types. Additionally, evaluation of the effects of TaNK cells on immune checkpoint blockade response showed that nonresponders had higher proportions of TaNK cells than responders. Further investigation into the interactions of NK cells with other immune cells in the tumor microenvironment (TME) revealed that most myeloid cells exhibit strong interactions with NK cells. Notably, among dendritic cell (DC) subsets, LAMP3⁺ DCs have the strongest interaction potential that leads to inhibition of CD56^dimCD16^hi cells in the TME. Finally, examination of the alterations in NK cells in the peripheral blood of patients with tumors indicated substantial cancer-specific transcriptome deviations compared to healthy donors, with high expression of MHC class II genes being noted, supporting the involvement of circulating NK cells in systemic immunity changes during tumor progression. In summary, this study presents a pan-cancer NK cell atlas that underscores the complexity of the antitumor activity of tumor-infiltrating NK cells, which can ultimately be applied to the development of NK cell–based immunotherapies.

Tang F, Li J, Qi L, Liu D, Bo Y, Qin S, et al. A pan-cancer single-cell panorama of human natural killer cells. Cell 2023 Aug 21 [Epub ahead of print].

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