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Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity
Xu Jiang. et al.
Signal Transduction and Targeted Therapy. 2024
In the growth and metastasis of malignant tumors such as breast cancer, macrophages have been found to exhibit immunosuppressive properties and participate in the formation of the pre-metastatic niche (PMN). In this study, researchers observed in a 4T1 breast cancer mouse model with spontaneous lung metastasis characteristics that no significant metastasis occurred during the early stages (within 18 days) after tumor cell inoculation, suggesting this period represents the formation phase of the PMN. During this time, the mRNA levels of the Ahr gene in lung macrophages showed dynamic changes, peaking on day 12, which was consistent with the transcriptional trends of AHR's major downstream genes, such as Cyp1a1, Cyp1b1, Nqo1, and Tsg6. The results further indicated that alveolar macrophages were the predominant macrophage subset in the lung PMN of tumor-bearing mice. The primary breast cancer tumors could release certain signals that activate AHR in lung macrophages, significantly enhancing its expression and nuclear localization. To verify the specific function of AHR, researchers used the Cre-Lox system to selectively knock out AHR in macrophages. The results showed that AHR knockout did not affect the growth of the primary breast tumor but significantly reduced lung metastasis and improved the survival rate of the mice. In macrophages lacking AHR in tumor-bearing mice, the levels of Treg cells in the PMN were significantly reduced, while the levels of other immune cell types in the PMN, such as CD8+ T cells, CD4+ T cells, NK cells, B cells, and neutrophils, were comparable to those in the control mice. Further results showed that GM-CSF secreted by breast cancer cells, after binding to its corresponding receptor on macrophages, activated the STAT5 signaling pathway, which inhibited the ubiquitination and degradation of AHR, thus stabilizing its expression and enhancing its activity. The activated AHR then translocated to the nucleus, where it interacted with nuclear translocation proteins and directly acted on the promoter of the PD-L1 encoding gene to promote its transcription. High expression of PD-L1 endowed macrophages with stronger immunosuppressive abilities, further inducing Treg cell differentiation, thereby enhancing the immunosuppressive properties of the PMN and promoting lung metastasis of breast cancer. The use of the AHR inhibitor CH223191 significantly reduced the expression of PD-L1 in macrophages. Additionally, in the 4T1 mouse model experiment, treatment with the STAT5 inhibitor STAT5-IN-1 reduced the levels of AHR in lung macrophages within the PMN.
DOI: 10.1038/s41392-024-02042-5
02
Wee Loong Chin. et al.
Cell Reports Medicine. 2024
In this paper, the authors enrolled 54 participants with previously untreated, unresectable pleural mesothelioma following durvalumab with chemotherapy as first-line treatment. To dissect out possible molecular signatures predictive of response in the DREAM cohort, they collected transcriptome data from both peripheral blood and tumor biopsies. This included bulk RNA sequencing (RNAseq) on peripheral whole blood from 40 participants at three time points (pre-treatment and prior to the second and third cycles of chemoimmunotherapy) and single-cell RNA-seq and single-cell TCR-seq on PBMCs at the same time points for 35 participants. They demonstrated substantial heterogeneity in patients’ responses to chemoimmunotherapy but also point to a subtle yet consistent difference in CD8 T cell differentiation between responders and nonresponders. Having shown that the CD8 + T EM cells were consistently more abundant in responders across time points, the authors next further characterized these cells in detail. They found three clusters that more abundant in responding participants at all time points. In these three subclusters, responders showed higher expression of genes associated with T cell activation including IRF1, EOMES, IFNG, major histocompatibility complex class I and II, and CD5, with larger differences in phenotype-specific gene expression at both time point 0 and time point 1 compared to time point 2. Furthermore, they distinguished characteristic of responding patients following chemoimmunotherapy is the high numbers of stem-like CD8 + T cells with a Tpex phenotype that persist over time. The expansion of the stem-like CD8 TEM compartment in responders was linked to a more permissive tumor microenvironment, with both gene expression in pre-treatment tumor and pre-treatment peripheral blood serving as surrogates to predict treatment response to chemoimmunotherapy in mesothelioma.
DOI: 10.1016/j.xcrm.2024.101882
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