A Human NK Cell Pan-Cancer Single-Cell Panorama

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Summary

In their study, they examined natural killer (NK) cells in the cancer environment using detailed single-cell RNA analyses from 716 cancer patients across 24 varieties. They discovered notable variations in NK cell types depending on the cancer. Importantly, they pinpointed a unique NK cell group with diminished tumor-fighting abilities linked to poor outcomes and immunotherapy resistance. The regulation of NK cells' cancer-fighting power seems to be influenced by specific myeloid cells, especially LAMP3+ dendritic cells. This research offers a deeper understanding of NK cells in cancer defense and emphasizes the potential therapeutic value of targeting specific NK cell groups.

Fig.1 Graphical abstract¹.

Research Criteria

The study involves integrative single-cell RNA sequencing analyses on natural killer (NK) cells from over 700 patients across 24 tumor types. The researchers aimed to depict the phenotypic and functional diversities of NK cells in the tumor microenvironment.

Fig.2 Experimental design¹.

Sample Type

Human liver tissues.

Result—Building a Human Pan-Cancer Model NK Cell Landscape at Single-Cell Resolution

In an ambitious endeavor to elucidate the intricacies of tumor-infiltrating NK cells, researchers have meticulously constructed a pan-cancer single-cell transcriptome atlas. Drawing from a vast pool of scRNA-seq data, encompassing 24 cancer types and 1,223 samples from 716 patients, they have successfully isolated a staggering 160,011 high-quality NK cells. This monumental atlas, which dwarfs its predecessors in scale, offers an unprecedented glimpse into the heterogeneity of NK cells within tumor tissues. Through rigorous computational analyses, the team delineated distinct NK cell subsets, each characterized by unique transcriptional signatures. Notably, these subsets exhibited varied developmental stages and functional divergences, with some showcasing heightened cytotoxic capabilities, while others were more attuned to cytokine production or immune cell recruitment. This groundbreaking work not only underscores the vast heterogeneity of NK cells but also paves the way for a more nuanced understanding of their roles in the intricate tumor microenvironment.

Fig.3 A pan-cancer single-cell NK cell atlas and its properties¹.

Result—The Features of Tumor-Associated NK Cell Programs

In a comprehensive study of tumor-associated NK cells, distinct characteristics of NK cells within tumors were illuminated. Compared to their counterparts in adjacent non-tumor tissue, these cells manifested a notable decrease in cytokine production, especially within the CD56^brightCD16^lo c3-CCL3 NK subset. Additionally, there was a decline in XCL1 and XCL2 expression in c5-CREM NK cells, hinting at functional shifts occurring within the tumor environment. Through the application of SCENIC, the research identified an elevated expression of transcription factors such as KLF6 and EGR3 in the tumor-enriched c6-DNAJB1 subset, which are conventionally associated with the curtailment of cytotoxic activities. RNA velocity analyses further charted a transcriptional progression from blood-enriched subsets towards tumor-infiltrating populations. Remarkably, the c6-DNAJB1 NK cells, designated as tumor-associated NK (TaNK) cells, predominantly populated the tumors. These TaNK cells, upon closer examination, exhibited diminished cytotoxic capacities and increased stress indicators, suggesting a potential state of dysfunction. This compromised state was further emphasized by their lowered expression of cytotoxic granules and augmented expression of inhibitory receptors. Conclusively, the research posits that these terminally dysfunctional TaNK cells may assume significant roles within the tumor microenvironment.

Fig.4 Tumor-associated NK cell characteristics¹.

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Reference

1. Tang, Fei, et al. "A pan-cancer single-cell panorama of human natural killer cells." Cell 186.19 (2023): 4235-4251.