Natural killer (NK) cells are a type of white blood cell that play a vital role in the human immune system. They specialize in detecting and destroying virus-infected or cancerous cells. Unlike other immune cells, NK cells can function without prior contact with target cells, making them an important first line of defense against new threats.
A research team led by Professor Tian Zhigang and Professor Peng Hui from the University of Science and Technology of China (USTC) at the Chinese Academy of Sciences (CAS), in collaboration with Professor Zhang Zemin from Peking University, elucidated the changes in natural killer (NK) cells in different cancer types and tissues. They identified a specific subpopulation of NK cells that exhibit abnormal anti-tumor functions and are particularly thriving in the tumor microenvironment. Their findings were recently published in the journal Cell.
Named for their ability to directly kill cancer cells, NK cells have become a strong competitor in immunotherapy, showing excellent efficacy in the treatment of blood cancers. However, the heterogeneity of NK cells, with varying phenotypes and functions in different tissue microenvironments, poses challenges to their application in the treatment of solid tumors.
For many years, Professor Tian and Professor Peng's teams have been studying the heterogeneity of NK cells in different tissues. In this study, the researchers collected an extensive single-cell transcriptome dataset spanning 24 cancer types, including a total of 1,223 samples from 716 patients and 47 healthy individuals. For the first time, they identified five different CD56brightCD16loNK cell subtypes and nine CD56dimCD16hiNK cell subtypes at a comprehensive pan-cancer level. The phenotypic and functional diversity of these isoforms has been carefully characterized.
By integrating this extensive data set, the researchers observed preferences for NK cell subtype composition across cancer types. Notably, the distribution of NK cell subtypes in tumors, adjacent tissues, and peripheral blood showed significant differences. Using advanced bioinformatics techniques, the researchers determined that the RGS1 gene is highly expressed in non-blood NK cells. At the transcriptional level, RGS1 shows significant specificity and sensitivity compared with traditional tissue-resident markers.
By probing the tumor microenvironment, the researchers found a group of DNAJB1+CD56dimCD16hiNK cells that were highly enriched in tumor problems. Analysis of this group revealed a dysfunctional phenotype with reduced cytotoxicity, increased inhibitory receptors, and elevated levels of stress-related proteins. This subtype is called "tumor-associated NK cells" (TaNK cells), and it subverts the traditional understanding that higher NK cell abundance is beneficial to cancer patients. In contrast, TaNK cells exhibit a strong association with poor prognosis in various cancer types and are significantly resistant to immunotherapy.
In addition, the researchers found that LAMP3+ dendritic cells (DCs) are key regulators of NK cell function. Spatial distribution data analysis showed that NK cells located close to LAMP3+DCs exhibited attenuated cytotoxic activity. This observation suggests that LAMP3+DC may exert abnormal regulation on NK cell function in the tumor microenvironment.