echemi logo
Product
  • Product
  • Supplier
  • Inquiry
    Home > Active Ingredient News > Antitumor Therapy > Nature: Ning Zhang/Zemin Zhang/Jiye Zhu collaborated to reveal immune microenvironment subtypes and neutrophil heterogeneity in liver cancer

    Nature: Ning Zhang/Zemin Zhang/Jiye Zhu collaborated to reveal immune microenvironment subtypes and neutrophil heterogeneity in liver cancer

    • Last Update: 2022-11-25
    • Source: Internet
    • Author: User
    Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

    At 0:00 a.
    m.
    Beijing time on November 10, 2022, Zhang Ning's team from the Cancer Translational Research Center of Peking University First Hospital, Zhang Zemin's team from Peking University Biomedical Frontier Innovation Center (BIOPIC) and Zhu Jiye's team from the Department of Hepatobiliary Surgery of Peking University People's Hospital published a report entitled "Liver tumor immune microenvironment subtypes and neutrophil" in Nature Heterogeneity"
    .

     

    This study defines for the first time the five immune microenvironment subtypes of liver cancer at single-cell accuracy, and is named the TIMELASER typing system, which comprehensively reveals the heterogeneity of tumor-associated neutrophils (TAN) for the first time, verifies the pro-tumor mechanism of two key subsets of CCL4+ and PD-L1+ TAN, and finally constructs a mouse liver cancer model from the three levels of In vitro, Ex vivo, and In vivo.
    It has been gradually proved that targeting tumor-associated neutrophils is expected to form a new immunotherapy regimen for liver cancer, and these achievements provide key information
    for basic research and clinical diagnosis and treatment of liver cancer.

     

     

    The heterogeneity of the immune microenvironment is one of
    the important reasons for tumor resistance, recurrence and poor prognosis.
    In recent years, immunotherapy and combination therapy have brought hope to patients with advanced tumors, and systematic exploration of the heterogeneity of tumor immune microenvironment has played an important guiding
    role in treatment selection, efficacy prediction, protocol optimization and development of new immunotherapy targets 。 In recent years, Zhang Ning's team at Peking University First Hospital has been focusing on the exploration of liver cancer heterogeneity, and revealed the genomic heterogeneity (Gastroenterology, 2016), phenotypic heterogeneity (Cancer Cell, 2019) and single-cell copy number heterogeneity of liver cancer (Gastroenterology, 2022)
    through a series of preliminary work.
    However, there is still a lack of systematic and in-depth exploration
    of the heterogeneity of the immune microenvironment of liver cancer.

     

    Previous studies have been based on pathological analysis or Bulk transcriptome sequencing, and the results have not accurately resolved their cellular composition and tend to ignore the small number of key cell subsets
    .
    The development of single-cell sequencing technology has promoted the exploration of tumor immunity, and a number of studies have explored liver cancer at the single-cell level
    .
    However, most of these studies have focused on specific types of cells, and their results do not reflect the full profile of
    the immune microenvironment.
    Therefore, there is an urgent need for unbiased research strategies that include all cell subtypes to systematically reveal the heterogeneity of
    the immune microenvironment of liver cancer.

     

    To unravel the characteristics of the tumor microenvironment in liver cancer, the researchers completed antibody-enriched, single-cell transcriptome sequencing of a total of 189 samples from humans and mice (Figure 1).

    At the same time, the researchers performed exome sequencing on the supporting cases, and collected 8 published single-cell transcriptome sequencing datasets, 453 tissue transcriptome sequencing and 10 spatial transcriptome data for verification and analysis, and comprehensively used tumor cell lines to construct the In vitro culture system, based on clinical samples to construct the Ex vivo experimental system, and based on the mouse tumor model In vivo experimental system for functional verification
    .

     

    Figure 1 Experimental design and cell subsets discovered in this study

     

    Five immune microenvironment subtypes of liver cancer

     

    First, the researchers systematically resolved 89 cell subsets
    of the immune microenvironment of liver cancer.
    Through hierarchical clustering analysis, the researchers successfully resolved five different immune microenvironment subtypes, including: (1) immune-activated TIME-IA (Immune Activation); (2) myeloid enrichment immunosuppressive TIME-ISM (Immune Suppressive Myeloid); (3) Matrix-enriched immunosuppressive TIME-ISS (Immune Suppressive Stromal); (4) Immune Exclusion (TIME-IE); (5) Immune Residence, collectively called the TIMELASER typing system (Figure 2).

    。 Subsequently, the researchers conducted multi-dimensional analysis of these five immune microenvironment subtypes, and verified the existence of the five subtypes through large-scale transcriptome data.
    The spatial distribution of cells of the five subtypes was revealed by spatial transcriptome data and CODEX multicolor immunoassay; Through receptor ligand analysis, it was found that each isotype had different chemokine receptor-ligand networks, suggesting the formation mechanism of different isoforms.
    Combined exon data analysis found that different subtypes enriched different driver gene mutations, such as TP53, CTNNB1, KRAS and IDH1, and found that different subtypes enriched different tumor cell gene modules
    .
    The discovery of these five immune microenvironments provides important reference information
    for tumor immunotherapy.

     

    FIG.
    2 SCHEMATIC DIAGRAM OF 5 SUBTYPES (TIMELASER) OF TUMOR IMMUNE MICROENVIRONMENT

     

    Functional heterogeneity of tumor-associated neutrophils

     

    Neutrophils are a very fragile class of cells that are generally considered to survive no more than a week after entering the body into the peripheral bloodstream and no more than 24 hours
    in vitro.
    Therefore, this population of cells
    has not been captured in previous single-cell studies of liver cancer.
    Thanks to the rapid experimental protocol and antibody-free enrichment strategy, more than 30,000 neutrophils
    were successfully captured.
    After cluster analysis, the researchers found a total of 11 subsets of neutrophils, which were enriched in peripheral blood, paracancer, and tumor tissues (Figure 3), and successfully identified 6 groups of tumor-associated neutrophils
    .
    Subsequently, the researchers analyzed the developmental trajectories and key transcription factors of these neutrophil subsets and found that two neutrophil subsets, CCL4+ TAN and PD-L1+ TAN, may promote tumor growth
    through different mechanisms 。 In order to further verify these findings, the researchers constructed the in vitro co-culture system of hepatoma cell line-neutrophils (In vitro) and the neutrophil ex vivo analysis system (Ex vivo) of liver cancer patients, and verified that CCL4+ TAN promotes tumor growth by recruiting tumor-associated macrophages through transcriptome sequencing, ATAC-seq and multicolor immunofluorescence

     

    Fig.
    3 Tissue distribution and developmental trajectories of neutrophil subsets

     

    A mouse model of liver cancer was constructed, revealing that the subpopulation of neutrophils was highly conserved with humans, and confirmed that removal of neutrophils could delay tumor growth

     

    In order to further explore the tumor-promoting mechanism of neutrophils in vivo, the researchers constructed two mouse liver cancer spontaneous tumor models (Myc-?) based on Alb-cre/Trp53fl/fl liver-specific knockout mice and liver cancer driver mutations (Myc-? 90Ctnnb1, pTMC; Myc-KrasG12D, pTMK), and analyzed for single-cell sequencing
    .
    The researchers found that the neutrophil subsets of mice were highly conserved compared with humans, which indicates that experiments using mouse liver cancer models can provide important reference information
    for the treatment of human liver cancer.
    Subsequently, the researchers used Anti-Ly6G antibodies to perform neutrophil removal experiments in mouse models, and the results showed that liver cancer growth in mice was effectively inhibited after treatment (Figure 4).

    Further, the researchers also revealed dynamic changes
    in neutrophil subsets in mouse bone marrow, peripheral blood, paracancer, and tumor tissue during treatment.
    These results suggest that the development of neutrophil-based immunotherapy targets is promising to lead to new therapeutic strategies
    for liver cancer.

     

    Fig.
    4 Anti-Ly6G antibody can effectively alleviate the growth of liver cancer in mice by removing neutrophils

     

    In summary, this study systematically revealed the immune microenvironment subtypes of liver cancer, and deeply analyzed the functional heterogeneity of tumor-associated neutrophils, and finally demonstrated that targeting tumor-associated neutrophils is expected to form a new immunotherapy strategy
    for liver cancer through mouse liver cancer models.
    The results indicate that interventions targeting tumor-associated centriolocyte are expected to significantly increase the number of patients effectively treated by immune checkpoints, which provides key information
    for basic research and clinical diagnosis and treatment of liver cancer and even solid tumors.

     

    XUE RUIDONG, ASSOCIATE RESEARCHER OF PEKING UNIVERSITY FIRST HOSPITAL, DR.
    ZHANG QIMING OF PEKING UNIVERSITY BIOPIC, CAO QI, DOCTORAL CANDIDATE OF PEKING UNIVERSITY FIRST HOSPITAL, ASSOCIATE RESEARCHER KONG RUIRUI OF PEKING UNIVERSITY FIRST HOSPITAL AND DR.
    XIANG XIAO OF PEKING UNIVERSITY PEOPLE'S HOSPITAL ARE THE JOINT FIRST AUTHORS
    OF THE PAPER.
    Professor Zhang Ning, Cancer Transformation Center, Peking University First Hospital, Professor Zhang Zemin of Peking University BIOPIC and Professor Zhu Jiye of Peking University People's Hospital are co-corresponding authors
    .

     

    The research was supported and funded
    by many national science foundations, such as the National Natural Science Foundation of China, the National Science and Technology Major Project of the 13th Five-Year Plan, the National Key Research and Development Program, and the Basic Science Center.

     

    Original source:

    Xue, R.
    , Zhang, Q.
    , Cao, Q.
    et al.
    Liver tumour immune microenvironment subtypes and neutrophil heterogeneity.
    Nature (2022).
    https://doi.
    org/10.
    1038/s41586-022-05400-x.

    This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.

    Related Articles

    Contact Us

    The source of this page with content of products and services is from Internet, which doesn't represent ECHEMI's opinion. If you have any queries, please write to service@echemi.com. It will be replied within 5 days.

    Moreover, if you find any instances of plagiarism from the page, please send email to service@echemi.com with relevant evidence.