Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy

Broad, Robyn; Jones, Stacey J.; Teske, Melina C.; Wastall, Laura M; Hanby, Andrew M.; Thorne, James L.; Hughes, Tom

doi:10.1038/s41416-020-01226-4

Cited by 38 publications

(31 citation statements)

References 46 publications

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“…Absorbance was assessed at 570 nm using a Mithras LB940 plate reader (Berthold; Bad Wildbad, Germany). Clonogenic survival assays were performed as described previously [ 24 ]. In brief, cells were transfected, treated with epirubicin, and reseeded at low density (100 MCF7 or 200 MDA-MB-175 cells per well of 6-well plates) in technical duplicates without further epirubicin.…”

Section: Methodsmentioning

confidence: 99%

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

Baxter

Allinson

Amri

et al. 2021

Cancers

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Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.

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Section: Methodsmentioning

confidence: 99%

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

Baxter

Allinson

Amri

et al. 2021

Cancers

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“…Activation of the type I IFNs (IFN-α/β) signaling pathway can cause cancer cell apoptosis and cellular senescence, and breast tumor cell secreted type I IFNs has been shown to induce anti-metastatic response. However, type I IFNs also attributed to drug resistance specifically in triple negative breast cancers (TNBC) and inflammatory breast cancer (IBC) ( 56 , 57 ). Type II IFNs (IFN-γ), on the other hand, has been reported to cause tissue damage in response to tumor hyperproliferation.…”

Section: Preclinical Studies Targeting Innate Immunity For Breast Cancer Therapymentioning

confidence: 99%

Targeting Innate Immunity in Breast Cancer Therapy: A Narrative Review

Chen

et al. 2021

Front. Immunol.

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Although breast cancer has been previously considered “cold” tumors, numerous studies are currently conducted to explore the great potentials of immunotherapies in improving breast cancer patient outcomes. In addition to the focus on stimulating adaptive immunity for antitumor responses, growing evidence showed the importance of triggering host innate immunity to eradicate established tumors and/or control tumor metastasis of breast cancer. In this review, we first briefly introduce the breast tumor immune microenvironment. We also discuss innate immune targets and pathways and mechanisms of their synergy with the adaptive antitumor response and other treatment strategies. Lastly, we review clinical trials targeting innate immune pathways for breast cancer therapies.

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“…Furthermore, independent prognostic factors were used to construct a nomogram to directly predict individual OS based on six CAFs-related-gene signature risk score (Figure 5). It was revealed that the main enriched pathways in the tumor, including epithelial-mesenchymal transformation (Shintani et al, 2016), hypoxia (Lappano et al, 2020), inflammatory Response (Ershaid et al, 2019), interferon-gamma response (Broad et al, 2021), and NFkB-mediated TNFα signal transduction (Katanov et al, 2015) were closely related to the function of CAFs. These observations indicate that risk scores can fully reflect the function of CAFs (Figure 6A).…”

Section: Discussionmentioning

confidence: 99%

Prognosis and Immunotherapy Significances of a Cancer-Associated Fibroblasts-Related Gene Signature in Gliomas

Chen

Zhuo

et al. 2021

Front. Cell Dev. Biol.

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As a cold tumor, malignant glioma has strong immunosuppression and immune escape characteristics. The tumor microenvironment (TME) provides the “soil” for the survival of malignant tumors, and cancer-associated fibroblasts (CAFs) are the architects of matrix remodeling in TME. Therefore, CAFs have potent regulatory effects on the recruitment and functional differentiation of immune cells, whereby they synthesize and secrete numerous collagens, cytokines, chemokines, and other soluble factors whose interaction with tumor cells creates an immunosuppressive TME. This consequently facilitates the immune escape of tumor cells. Targeting CAFs would improve the TME and enhance the efficacy of immunotherapy. Thus, regulation of CAFs and CAFs-related genes holds promise as effective immunotherapies for gliomas. Here, by analyzing the Chinese Glioma Genome Atlas and the Cancer Genome Atlas database, the proportion of CAFs in the tumor was revealed to be associated with clinical and immune characteristics of gliomas. Moreover, a risk model based on the expression of CAFs-related six-gene for the assessment of glioma patients was constructed using the least absolute shrinkage and selection operator and the results showed that a high-risk group had a higher expression of the CAFs-related six-genes and lower overall survival rates compared with those in the low-risk group. Additionally, patients in the high-risk group exhibited older age, high tumor grade, isocitrate dehydrogenase wildtype, 1p/19q non-codeletion, O-6-methylguanine-DNA methyltransferase promoter unmethylation and poor prognosis. The high-risk subtype had a high proportion CAFs in the TME of glioma, and a high expression of immune checkpoint genes. Analysis of the Submap algorithm indicated that the high-risk patients could show potent response to anti-PD-1 therapy. The established risk prediction model based on the expression of six CAFs-related genes has application prospects as an independent prognostic indicator and a predictor of the response of patients to immunotherapy.

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Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy

Abstract: This is a repository copy of Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy.

Cited by 38 publications

References 46 publications

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

Targeting Innate Immunity in Breast Cancer Therapy: A Narrative Review

Prognosis and Immunotherapy Significances of a Cancer-Associated Fibroblasts-Related Gene Signature in Gliomas

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