Cancer Cell Liu Zhihua/Zhang Zemin/Ma Fei/Xu Binghe collaborated to reveal the mechanism of action of Anti-PD-L1 immunotherapy combined with chemotherapy in triple-negative breast cancer

Editor | xi 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
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TNBC is ineffective against hormone therapy and targeted therapy.
At present, traditional chemotherapy is the main treatment method, but the effect is not satisfactory
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Although cancer immunotherapy has entered a period of rapid development, TNBC immunotherapy is difficult: Although early clinical trials of IMpassion 130 have shown that the 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, the recent clinical trial of IMpassion 131 showed that atilizumab combined with paclitaxel could not benefit TNBC patients
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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
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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
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On October 14, 2021, 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 cooperated online in Cancer Cell as Research Article Published a research paper entitled Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple negative breast cancer
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Researchers on this subject collected 78 paired samples from 22 TNBC patients (11 received atelizumab 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)
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The research system compared the tumor microenvironment and peripheral blood immune characteristics of responding patients and non-responding patients, clarified the dynamic changes of immune cells under different treatment plans, and revealed the effect of anti-PD-L1 immunotherapy combined with paclitaxel chemotherapy in TNBC Mechanism of action
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Figure 1 The project research plan By comparing the composition of the tumor and peripheral blood immune cells of different responders in the combination drug 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), these two groups of cells simultaneously highly express T cell toxicity and "depletion" related genes
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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
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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
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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
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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
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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 (Figure 2), suggesting that the peripheral blood can to a certain extent Reflect the characteristics of the tumor microenvironment
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Figure 2 Tumor microenvironment characteristics of patients with different responses in immunotherapy combined with chemotherapy 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.
Together determine the occurrence and development of cancer
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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
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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
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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
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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
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By comparing the dynamic changes of immune cells in the chemotherapy group and the combination drug group, the researchers found that in contrast to the combination drug, paclitaxel single-agent chemotherapy can significantly reduce the response to CXCL13+ T cells in the tumor microenvironment of the patient, and cause macrophages with immunosuppressive function.
Cells are enriched in the tumor microenvironment (Figure 3)
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The above findings indicate that paclitaxel chemotherapy regimens may weaken core anti-tumor immune cells, while immune checkpoint inhibitors can significantly increase core anti-tumor immune cells, suggesting that paclitaxel chemotherapy regimens can affect anti-tumor effects when combined with atilizumab.
The therapeutic effect of PD-L1 antibody on TNBC patients
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Figure 3 The effects of different treatment options on the TNBC tumor microenvironment.
In summary, this study revealed the molecular mechanism of TNBC patients' sensitivity and resistance to anti-PD-L1 immunotherapy, and identified key immune components and their suppression at immune checkpoints The dynamic changes under the chemotherapy regimen of paclitaxel and paclitaxel clarified the reason why the combination of paclitaxel chemotherapy and atilizumab could not effectively increase the therapeutic effect of TNBC patients
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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
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It is reported that this internationally leading novel work is the largest single-cell omics study on TNBC tumor-related immune cells in the world so far, providing a deep understanding of the immune characteristics of TNBC patients and the mechanism of action of immunotherapy combined with chemotherapy.
It has established a reliable foundation and provided extremely valuable data resources for subsequent related research work
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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
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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
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Dr.
Zhang Yuanyuan, postdoctoral fellow from 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
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Original link: https://doi.
org/10.
1016/j.
ccell.
2021.
09.
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