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This article is the original of Translational Medicine Network, please indicate the source for reprinting
Written by Jevin
Summary: The heterogeneity of the immune microenvironment is one of
the important reasons for tumor drug resistance, recurrence and poor prognosis.
In recent years, immunotherapy and related combination therapy regimens 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.
However, at present, scientists still lack systematic and in-depth understanding
of the heterogeneity of the immune microenvironment of liver cancer.
On November 10, 2022, the team of Zhang Ning, the Cancer Transformation Research Center of Peking University First Hospital, the team of Zhang Zemin of the Biomedical Frontier Innovation Center of Peking University, and the team of Zhu Jiye of the Department of Hepatobiliary Surgery of Peking University People's Hospital published a research paper
in Nature.
The study is the first to define five immune microenvironment subtypes of liver cancer at single-cell precision and named them the TIMELASER typing system, in addition, the study is the first to comprehensively reveal the heterogeneity
of tumor-associated neutrophils.
style="box-sizing: border-box;" _msthash="251139" _msttexthash="1981148">Five immune microenvironment subtypes of liver cancer
01
The researchers systematically resolved 89 cell subsets of the immune microenvironment of liver cancer, among which 11 previously unreported neutrophil subsets
were also discovered for the first time.
The researchers found that these cell subsets were not evenly distributed
between different cases.
Through hierarchical clustering analysis, the researchers successfully resolved 5 different immune microenvironment subtypes, including: immunoactivatory, myeloid enrichment immunosuppressive, stromal-enriched immunosuppressive, immunorejective and immune-resident type, which are collectively called the TIMELASER typing system
.
Subsequently, the researchers conducted a multidimensional analysis of these five immune microenvironment subtypes, verified the existence of the five subtypes by analyzing large-scale transcriptome data, and suggested the formation mechanism
of different subtypes.
Cluster analysis for more than 30,000 neutrophils
02
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 process and antibody-free enrichment strategy, the Peking University research team successfully captured more than 30,000 neutrophils
.
After cluster analysis, the researchers found a total of 11 subsets of neutrophils, which were enriched in peripheral blood, paracancerous and tumor tissues, 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.
A series of experiments have verified that CCL4+ TAN promotes tumor growth by recruiting tumor-associated macrophages, while PD-L1+ TAN promotes tumor growth
by inhibiting the killing function of CD8+ T cells.
Neutrophil-based immunotherapeutic targets
03
In order to further explore the tumor-promoting mechanism of neutrophils in vivo, the researchers constructed two spontaneous tumor models of liver cancer in mice and analyzed them by 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 antibody to perform neutrophil removal experiments in mouse models, and the results showed that the growth of liver cancer in mice was effectively inhibited
after treatment.
These results suggest that the development of neutrophil-based immunotherapy targets holds promise for the formation of new therapeutic strategies
for liver cancer.
In addition, further exploration of the influence of neutrophils on immunotherapy and related confounding clinical factors will provide new opportunities for a better understanding of TAN biology and propose translational research pathways
for liver cancer treatment.
Resources:
style="white-space: normal;box-sizing: border-box;">Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.
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