Tumor-Infiltrating Human NK Cell Atlas Created

Researchers from the University of Science and Technology of China (USTC), in collaboration with Peking University, have unveiled the diverse nature of natural killer (NK) cells in different cancer types and tissues. Through the construction of a comprehensive tumor-infiltrating human NK cell atlas and exploration of the heterogeneity of NK cells across cancer types and tissues, their study, published in Cell, identified a subset of NK cells with altered anti-tumor functions that thrive specifically within the tumor microenvironment.

NK cells, known for their ability to directly target and kill cancer cells, have shown remarkable effectiveness in blood cancer treatments. However, the heterogeneity of NK cells, which exhibit varying phenotypes and functions within distinct tissue microenvironments, poses challenges in their application for solid tumor therapy.

In this extensive study, the team, which has been investigating the heterogeneity of NK cells across various tissues, collected single-cell transcriptome data from 24 cancer types, including 1,223 samples from 716 patients and 47 healthy individuals. They identified five distinct subtypes of CD56brightCD16lo NK cells and nine subtypes of CD56dimCD16hi NK cells at a comprehensive pan-cancer level for the first time. These subtypes were thoroughly characterized based on their phenotypic and functional diversity.

The study revealed variations in the composition of NK cell subtypes across different cancer types, with significant differences observed in their distribution within tumors, neighboring tissues, and peripheral blood. The researchers also identified the gene RGS1, highly expressed in non-blood NK cells, as a potential marker for tissue residency, demonstrating specificity and sensitivity compared to conventional markers.

Within the tumor microenvironment, the researchers discovered a subgroup of NK cells named "tumor-associated NK cells" (TaNK cells) that exhibited a dysfunctional phenotype, characterized by reduced cytotoxicity, increased inhibitory receptors, and elevated stress-related protein levels. TaNK cells were strongly associated with unfavorable prognoses in various cancer types and displayed resistance to immunotherapy.

Additionally, the study highlighted the role of LAMP3+ dendritic cells (DCs) as critical regulators of NK cell functionality. NK cells in close proximity to LAMP3+ DCs exhibited diminished cytotoxic activity, suggesting that these DCs may exert abnormal regulatory effects on NK cell function within the tumor microenvironment.

This research provides valuable insights into the heterogeneity of NK cells and their complex interactions within tumors, shedding light on potential challenges in developing effective immunotherapies for solid tumors.