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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 and phenotypic heterogeneity of liver cancer (Cancer Cell, 2019) through a series of preliminary work and single-cell copy number heterogeneity (Gastroenterology, 2022).
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.
On November 10, 2022, Zhang Ning's team from the Cancer Translational Research Center of Peking University First Hospital and Zhang Zemin of the Biomedical Frontier Innovation Center (BIOPIC) of Peking University The team, Zhu Jiye, Department of Hepatobiliary Surgery, Peking University People's Hospital, worked closely together and published a report in Nature entitled: Liver tumor immune microenvironment subtypes and neutrophil Research paper
by Heterogeneity.
This study is the first to define five immune microenvironment subtypes of liver cancer at single-cell accuracy and is named the TIMELASER typing system, which is the first to comprehensively reveal the heterogeneity of tumor-associated neutrophils (TAN) and validate CCL4 +, PD-L1+TAN, the two key subsets of tumor-promoting mechanism, finally through the construction of mouse liver cancer model, from the three levels of In vitro, Ex vivo, In vivo gradually proved that targeting tumor-associated neutrophils is expected to form a new liver cancer immunotherapy regimen.
These results provide key information
for basic research and clinical diagnosis and treatment 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: The experimental design of this study and the discovery of five immune microenvironment
subtypes of cellular subsets
of liver cancer First, The researchers systematically analyzed 89 cell subsets
of the immune microenvironment of liver cancer.
Through hierarchical cluster 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 (Immune Exclusion); (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 with exon data analysis, different subtypes were enriched with different driver gene mutations, such as TP53, CTNNB1, KRAS and IDH1, and different subtypes were enriched with different tumor cell gene modules.
The discovery of these five immune microenvironments provides important reference information
for tumor immunotherapy.
Figure 2: Schematic diagram
of the functional heterogeneity
of tumor-associated neutrophils with 5 subtypes (TIMELASER) of the tumor immune microenvironment 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, paracancerous 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.
To further validate these findings, the researchers constructed a hepatoma cell line-neutrophil in vitro co-culture system (In vitro) and an ex vivo analysis system for neutrophils in liver cancer patients Transcriptome sequencing, ATAC-seq and multicolor immunofluorescence confirmed that CCL4+TAN promotes tumor growth by recruiting tumor-associated macrophages, while PD-L1+TAN inhibits CD8</The killing function of b183> of neutrophil subsets constructed two mouse spontaneous tumor models of liver cancer (Myc-∆90Ctnnb1) based on Alb-cre/Trp53 of liver cancer in mice by removing neutrophils
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 and phenotypic heterogeneity of liver cancer (Cancer Cell, 2019) through a series of preliminary work and single-cell copy number heterogeneity (Gastroenterology, 2022).
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.
On November 10, 2022, Zhang Ning's team from the Cancer Translational Research Center of Peking University First Hospital and Zhang Zemin of the Biomedical Frontier Innovation Center (BIOPIC) of Peking University The team, Zhu Jiye, Department of Hepatobiliary Surgery, Peking University People's Hospital, worked closely together and published a report in Nature entitled: Liver tumor immune microenvironment subtypes and neutrophil Research paper
by Heterogeneity.
This study is the first to define five immune microenvironment subtypes of liver cancer at single-cell accuracy and is named the TIMELASER typing system, which is the first to comprehensively reveal the heterogeneity of tumor-associated neutrophils (TAN) and validate CCL4 +, PD-L1+TAN, the two key subsets of tumor-promoting mechanism, finally through the construction of mouse liver cancer model, from the three levels of In vitro, Ex vivo, In vivo gradually proved that targeting tumor-associated neutrophils is expected to form a new liver cancer immunotherapy regimen.
These results provide key information
for basic research and clinical diagnosis and treatment 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: The experimental design of this study and the discovery of five immune microenvironment
subtypes of cellular subsets
of liver cancer First, The researchers systematically analyzed 89 cell subsets
of the immune microenvironment of liver cancer.
Through hierarchical cluster 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 (Immune Exclusion); (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 with exon data analysis, different subtypes were enriched with different driver gene mutations, such as TP53, CTNNB1, KRAS and IDH1, and different subtypes were enriched with different tumor cell gene modules.
The discovery of these five immune microenvironments provides important reference information
for tumor immunotherapy.
Figure 2: Schematic diagram
of the functional heterogeneity
of tumor-associated neutrophils with 5 subtypes (TIMELASER) of the tumor immune microenvironment 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, paracancerous 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.
To further validate these findings, the researchers constructed a hepatoma cell line-neutrophil in vitro co-culture system (In vitro) and an ex vivo analysis system for neutrophils in liver cancer patients Transcriptome sequencing, ATAC-seq and multicolor immunofluorescence confirmed that CCL4+TAN promotes tumor growth by recruiting tumor-associated macrophages, while PD-L1+TAN inhibits CD8</The killing function of b183> of neutrophil subsets constructed two mouse spontaneous tumor models of liver cancer (Myc-∆90Ctnnb1) based on Alb-cre/Trp53 of liver cancer in mice by removing neutrophils
