On March 5, Zhang Xiaoming, a researcher of the Chinese Academy of Sciences Shanghai Institute of Immunology and Infection, Gao Qiang, a professor of the Sun Yat sen Hospital affiliated to Fudan University, Fan Jia, an academician of the CAS Member, and Yang Li, a researcher of the Institute of Biomedical Research of Fudan University, published a research paper on Cell entitled Neutral proliferating illuminates anti tumor antigen responding potential, Revealed the anti-tumor properties and molecular regulatory mechanisms of MHCII+neutrophils with antigen presentation ability.

Neutrophils are the most abundant type of white blood cells in the human body, accounting for 40% to 70% of the body's white blood cells. As the first line of defense of natural immunity, neutrophils play a crucial role in anti infection immunity. A study has found that neutrophils are widely involved in the process of tumor occurrence, development, and prognosis, and are an important component of the tumor microenvironment. However, whether neutrophils play an anti-tumor or pro tumor role is one of the controversial focuses in the field of tumor immunity. The short half-life, fragility, and low overall gene expression abundance of neutrophils have led to a lack of large-scale systematic research on human neutrophils. In recent years, the rapid development of single-cell multi omics technology has brought new opportunities for in-depth research on the phenotype, function, and mechanism of neutrophils at the pan cancer scale.

This study integrated single-cell transcriptome data of neutrophils from a total of 225 patient samples from 17 types of cancer, including liver cancer, bile duct cancer, and gallbladder cancer (with self-test data accounting for 79.29%). Through cluster analysis, it was found that neutrophils can be divided into 10 major groups, such as HLA-DR+CD74+antigen presenting type, VEGFA+SPP1+pro angiogenic type, and CXCL8+IL1B+inflammatory type. These neutrophils correspond to different immune phenotypes, chemokine characteristics, and maturation states. Among multiple types of cancer, HLA-DR+CD74+neutrophils are associated with good prognosis, while VEGFA+SPP1+neutrophils are associated with poor prognosis. The study characterized the different maturation states of neutrophils by comprehensively utilizing four single-cell trajectory algorithms, multiple immunofluorescence, flow cytometry, and other technologies. It was found that HLA-DR+CD74+neutrophils are in a mature state of terminal differentiation.

This work further focuses on the study of the function and regulatory mechanism of HLA-DR+CD74+neutrophils. Through single-cell metabolic pathway analysis and small-scale metabolite screening in vitro, it was found that leucine can upregulate the expression of MHC-II antigen presenting molecules and related co stimulatory molecules in neutrophils. Molecular level studies have found that leucine enhances the generation of acetyl CoA and H3K27 acetylation modification in the promoter region of MHC-II molecules through mitochondrial structural and functional remodeling, leading to upregulation of antigen-presenting molecules such as HLA-DR. Correspondingly, research has found that HLA-DR+CD74+neutrophils can present tumor neoantigens to T cells, reshape the T cell immune repertoire, and enhance antigen-specific responses. This reveals the metabolic plasticity and immune promoting function of HLA-DR+CD74+neutrophils.

On this basis, the study explored the anti-tumor therapeutic value of antigen-presenting neutrophils. Research has shown that various types of mouse tumors have CD74+antigen-presenting neutrophil subpopulations. In mouse models, a diet rich in leucine or CD74+neutrophil adoptive therapy can enhance the efficacy of anti PD-1 immunotherapy. When antigen-presenting neutrophils were used for adoptive treatment of patient derived tumor tissue in vitro, both T cell antigen-specific reactive molecules and killer molecules were significantly increased. In addition, based on the analysis of immunotherapy sequencing data from tumor patients, it was found that the abundance of antigen-presenting neutrophils is significantly positively correlated with the degree of immunotherapy response.

The above study generated a cross cancer neutrophil transcriptome big dataset, analyzing cancer specific and common neutrophil transcriptional patterns, cell states, metabolic characteristics, and clinical relevance. It elucidated the antigen presentation function and molecular mechanism of HLA-DR+CD74+neutrophils, and discovered the characteristics of antigen-presenting neutrophils that induce T cell antigen-specific reactions and promote anti-tumor immune responses, Revealed the potential of antigen-presenting neutrophils as a novel immunotherapy strategy.

Paper link:论文链接



Heterogeneity of neutrophil subpopulations in tumor microenvironment and the anticancer potential of antigen-presenting neutrophils