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    Home > Biochemistry News > Biotechnology News > Cancer Cell Chinese scholars reveal the mechanism of action of Anti-PD-L1 immunotherapy combined with chemotherapy in triple-negative breast cancer

    Cancer Cell Chinese scholars reveal the mechanism of action of Anti-PD-L1 immunotherapy combined with chemotherapy in triple-negative breast cancer

    • Last Update: 2021-11-11
    • Source: Internet
    • Author: User
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    Breast cancer ranks first among female malignant tumors.
    Triple-Negative Breast Cancer (TNBC) is the subtype of breast cancer with the highest recurrence rate and mortality rate

    .
    TNBC is ineffective against hormone therapy and targeted therapy.
    At present, traditional chemotherapy is the main treatment method, but the effect is not satisfactory

    .
    Although cancer immunotherapy has entered a period of rapid development, TNBC immunotherapy is difficult: Although early clinical trials of IMpassion 130 have shown that anti-PD-L1 antibody Atezolizumab (Atezolizumab) combined with albumin-bound paclitaxel (Nab-paclitaxel) ) Can significantly reduce the risk of disease-free progression or death in PD-L1+ TNBC patients.
    However, recent clinical trials of IMpassion 131 have shown that atilizumab combined with paclitaxel cannot benefit TNBC patients

    .
    The differences in the results of different clinical trials suggest that different chemotherapeutic drugs may lead to different tumor microenvironment characteristics, which in turn affects the therapeutic effect of immune checkpoint inhibitors

    .
    Systematic analysis of the changes in the tumor microenvironment before and after medication is the key to understanding the current mechanism of immunotherapy and chemotherapy drugs and improving the overall therapeutic effect of TNBC

    .


    On October 14, 2021, the international journal Cancer Cell published an online research titled "Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple negative breast cancer" from a Chinese scholar in the form of a Research Article.
    Thesis

    .
    Researchers on this subject collected 78 paired samples from 22 TNBC patients (11 received atilizumab combined with paclitaxel chemotherapy, 11 received paclitaxel single-agent chemotherapy) before and after treatment, by integrating single-cell transcription Group sequencing, T cell receptor sequence sequencing, and chromatin access sequencing, constructed a high-resolution transcriptome and epigroup dynamic map of TNBC patients' tumor microenvironment and peripheral blood-derived immune cells (Figure 1)

    .
    The research system compared the tumor microenvironment and peripheral blood immune characteristics of responding and non-responding patients, clarified the dynamic changes of immune cells under different treatment options, and revealed the effect of anti-PD-L1 immunotherapy combined with paclitaxel chemotherapy in TNBC Mechanism of action

    .

     

    Figure 1 Project research plan


    By comparing the differences in the composition of tumors and peripheral blood immune cells of different responders in the combination therapy group, the researchers found that the tumor microenvironment of the responding patients was enriched in two groups of T cells with high expression of CXCL13 (CD8-CXCL13 and CD4-CXCL13).
    Both groups of cells simultaneously highly express T cell toxicity and "depletion" related genes

    .
    In order to further accurately describe the relationship between changes in the composition and ratio of different immune cells and treatment effects, the researchers designed two indexes: "predictive index" and "therapeutic index".
    Through the analysis of "predictive index" and "therapeutic index", research The researchers found that higher baseline levels of CD8-CXCL13 and CD4-CXCL13 can predict better immunotherapy response, and that the proportion of these two groups of CXCL13+ T cells in response patients increased significantly after the combination therapy (Figure 2)

    .
    It is worth noting that the researchers found that in contrast to the combination therapy, paclitaxel single-agent chemotherapy can significantly reduce the CXCL13+ T cells in the tumor microenvironment of responding patients, and lead to the enrichment of immunosuppressive macrophages in the tumor microenvironment

    .

     

    Figure 2 Dynamic changes of T cell subsets under different treatment options


    In addition, the researchers found that the tumor microenvironment of the responding patients was enriched in two groups of pro-inflammatory macrophages with high expression of CXCL9 and CXCL10, and there was a significant positive correlation between these two groups of pro-inflammatory macrophages and CXCL13+ T cells (Figure 3)
    .
    CXCL9 and CXCL10 can participate in T cell recruitment, and the characteristic genes of pro-inflammatory macrophages are regulated by IFNG and TNF signals, indicating that there is a relationship between CXCL13+ T cells with killing function and pro-inflammatory macrophages with high expression of CXCL9 and CXCL10 Positive feedback signal

    .
    In contrast, CXCL13+ T cells are almost undetectable in the tumor microenvironment of non-responsive patients, but a large number of macrophages that exert immunosuppressive functions are enriched

    .
    It is worth noting that the researchers found that the peripheral blood mononuclear cells of the responding patients showed pro-inflammatory characteristics, while the peripheral blood mononuclear cells of the non-responsive patients showed anti-inflammatory characteristics, suggesting that the peripheral blood can reflect the tumor microenvironment to a certain extent.
    Features

    .


    Figure 3 Tumor microenvironment and characteristics of myeloid cells in peripheral blood of TNBC patients


    The tumor microenvironment is a complex ecosystem, in which innate immune and adaptive immune cells, stromal cells, cancer cells and their interactions constitute a fine regulatory network that together determine the occurrence and development of cancer
    .
    Although T cells are the focus of current tumor immunity research, other types of immune cells can also affect the effect of immunotherapy through regulation or interaction with T cells

    .
    By systematically characterizing the proportion and dynamic changes of immune cells, the researchers found that B cells, especially follicular B cells, were significantly enriched in the tumor microenvironment of responding patients, and they increased significantly after immunotherapy

    .
    Further through correlation analysis and ligand-receptor interaction pair co-expression analysis, the researchers found that follicular B cells and CXCL13+ T cells are significantly positively correlated and interact (Figure 4)

    .
    In addition, based on the cell composition at the single cell level and the characteristic gene expression of TCGA public data, the researchers found that cDC1 is significantly positively correlated with CXCL13+ T cells, and cDC1 is significantly increased under the action of immunotherapy, suggesting that cDC1 may be involved in the activation of CXCL13+ T cells

    .


    Figure 4 Dynamic changes of B cells and DC subgroups and their association with CXCL13+ T cells


    The first author of the paper, Dr.
    Yuanyuan Zhang, said that this study revealed the molecular mechanism of TNBC patients' sensitivity and resistance to anti-PD-L1 immunotherapy, and identified key immune components and their effects under immune checkpoint inhibitors and paclitaxel chemotherapy regimens.
    The dynamic changes clarify the reason why the combination of paclitaxel chemotherapy and atilizumab cannot effectively increase the therapeutic effect of TNBC patients

    .
    The research results of this subject have important guiding significance for the current immunotherapy combined chemotherapy regimen, suggesting that further systematic evaluation of the molecular mechanism of the combined use of different chemotherapeutic drugs and immunotherapeutic drugs is needed to effectively improve the therapeutic effect of the combination regimen on TNBC patients

    .

    It is reported that this study is the largest single-cell omics study on TNBC tumor-related immune cells in the world so far.
    It provides a reliable basis for in-depth understanding of the immune characteristics of TNBC patients and the mechanism of action of immunotherapy combined with chemotherapy regimens, and also provides a reliable basis for follow-up Related research work provides extremely valuable data resources

    .
    The scientific findings of this research provide new ideas for analyzing the dynamic regulation of immune cells in tumors and other diseases, guiding the clinical classification of TNBC patients to achieve precise treatment, and developing new clinical detection and treatment methods

    .

    Professor Liu Zhihua from Cancer Hospital of Chinese Academy of Medical Sciences, Professor Zhang Zemin from Peking University Biomedical Frontier Innovation Center (BIOPIC), Professor Ma Fei and Professor Xu Binghe from Cancer Hospital of Chinese Academy of Medical Sciences are the co-corresponding authors of the paper
    .
    Zhang Yuanyuan, postdoctoral fellow at the Peking University-Tsinghua Joint Center for Life Sciences (CLS), Dr.
    Hongyan Chen and Dr.
    Hongnan Mo from the Cancer Hospital of the Chinese Academy of Medical Sciences, and Dr.
    Xueda Hu from Baiao Zhihui are the co-first authors of the paper

    .
    The research was supported and funded by the Beijing Municipal Science and Technology Commission, the National Natural Science Foundation of China, and the National Key Research and Development Program

    .
    Link to the paper: https://

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