Tumor "natural killer"! New progress in NK cell research at USTC

Natural Killer (NK) cells are important members of the immune system and are known as natural killers of tumors. They are named for their ability to directly kill tumor cells. In recent years, with the rise of tumor immunotherapy, NK cell-based immunotherapy has become an emerging main force, shining in the field of hematological tumor treatment, but the treatment of solid tumors has been slow. Because NK cells are a heterogeneous group, they are composed of different subgroups with different phenotypes and functions in different tissue microenvironments. Therefore, a comprehensive and systematic study of NK cells in tumor tissues is conducive to clearing obstacles for NK cell immunotherapy.

For many years, the research groups of Tian Zhigang and Peng Hui from the University of Science and Technology of China have focused on the tissue heterogeneity of NK cells and discovered special NK cell populations in tissues such as the liver, intestine, and skin. Recently, in collaboration with the research group of Zhang Zemin from Peking University, they have systematically characterized the heterogeneity of NK cells between different cancer types and tissues, discovered NK cell subtypes that are specifically enriched in the tumor microenvironment and have abnormal killing functions, and revealed the potential regulatory relationship between NK cells and other components in the microenvironment .

The research results were published online in Cell on August 21 with the title "A Pan-Cancer Single Cell Panorama of Human Natural Killer Cells". In this study, Professor Peng Hui of our school is the co-corresponding author.

The researchers collected and organized a large amount of public single-cell transcriptome data involving 24 cancer types, including single-cell expression profile data of NK cells from 1,223 samples from 716 patients and 47 healthy controls. For the first time, they systematically identified 5 types of CD56brightCD16lo and 9 types of CD56dimCD16hi NK cell subsets at the pan-cancer level, and characterized the phenotypic and functional diversity of each population in detail.

Based on the integrated data resources, the researchers found that the subpopulation composition of NK cells showed obvious preference among different cancer types, and the distribution of NK cell subtypes in tumors, adjacent tissues and peripheral blood also showed obvious differences. Through bioinformatics screening, it was found that RGS1 was specifically highly expressed on non-blood-derived NK cells.

Compared with classic tissue-resident signature genes, RGS1 showed higher specificity and sensitivity at the transcriptome level, and had excellent performance at the pan-cancer level. Focusing further on the tumor microenvironment, the researchers found that a group of DNAJB1+ CD56dimCD16hi NK cells were highly enriched in tumor tissues. Data analysis found that this group of cells had a dysfunctional phenotype, including decreased cytotoxicity, increased inhibitory receptors, and high expression of stress response-related proteins, so they were named tumor-associated NK cells (TaNK cells).

Different from the classical understanding that a higher abundance of NK cells is beneficial to the survival of cancer patients, the enrichment of TaNK cells is significantly associated with poor prognosis of multiple cancer types and resistance to immunotherapy. These findings indicate that TaNK cells have important biological and clinical application value, and provide new ideas for the subsequent development of NK cell-related immunotherapy methods.

In addition, the researchers found that myeloid cells, especially LAMP3+ DCs, are important regulatory factors for NK cells. Further bioinformatics analysis combined with spatial distribution quantification revealed that NK cells close to LAMP3+ DCs showed lower killing activity, indicating that LAMP3+ DCs have a potential abnormal regulatory effect on NK cell function in the tumor immune microenvironment.

Schematic diagram of the main findings of the study

In summary, this work innovatively integrated and utilized large-scale single-cell data, revealing changes in gene expression patterns in NK cells and capturing changes in NK cell subset composition in the tumor immune microenvironment. This will help explore new biomarkers and therapeutic targets through more comprehensive integrated analysis methods in the future, and also provide more accurate and comprehensive data support for drug development .