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Activin A Promotes Regulatory T-cell-Mediated Immunosuppression in Irradiated Breast Cancer.

ABSTRACT: Increased regulatory T cells (Treg) after radiotherapy have been reported, but the mechanisms of their induction remain incompletely understood. TGFβ is known to foster Treg differentiation within tumors and is activated following radiotherapy. Thus, we hypothesized that TGFβ blockade would result in decreased Tregs within the irradiated tumor microenvironment. We found increased Tregs in the tumors of mice treated with focal radiotherapy and TGFβ blockade. This increase was mediated by upregulation of another TGFβ family member, activin A. In vitro, activin A secretion was increased following irradiation of mouse and human breast cancer cells, and its expression was further enhanced upon TGFβ blockade. In vivo, dual blockade of activin A and TGFβ was required to decrease intratumoral Tregs in the context of radiotherapy. This resulted in an increase in CD8⁺ T-cell priming and was associated with a reduced tumor recurrence rate. Combination of immune checkpoint inhibitors with the dual blockade of activin A and TGFβ led to the development of tumor-specific memory responses in irradiated breast cancer. Supporting the translational value of activin A targeting to reduce Treg-mediated immunosuppression, retrospective analysis of a public dataset of patients with breast cancer revealed a positive correlation between activin A gene expression and Treg abundance. Overall, these results shed light on an immune escape mechanism driven by activin A and suggest that dual targeting of activin A and TGFβ may be required to optimally unleash radiation-induced antitumor immunity against breast cancer.

SUBMITTER: De Martino M

PROVIDER: S-EPMC7785684 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Activins belong to the transforming growth factor-? (TGF-?) superfamily of cytokines. Although the role of TGF-? in cancer progression has been highly advocated, the role of activin signaling in cancer is not well known. However, overexpression of activin-A has been observed in several cancers. AIMS:The gene expression profile indicated higher expression of Activin-A in breast tumors. Hence the aim of this study was to evaluate the status and role of Activin signaling pathway in these tumors. METHODS:Microarray analysis was performed to reveal gene expression changes in breast tumors. The results were validated by quantitative PCR and immunohistochemical analysis in two independent sets of normal and tumor samples. Further, correlation of activin expression with survival and distant metastasis was performed to evaluate its possible role in tumor progression. We used recombinant activin-A, inhibitors, overexpression, and knockdown strategies both in vitro and in vivo, to understand the mechanism underlying the protumorigenic role of this signaling pathway. RESULTS:We report that activin-A signaling is hyperactivated in breast cancers as indicated by higher activin-A, phosphoSMAD2, and phosphoSMAD3 levels in advanced breast cancers. Bone morphogenetic proteins and molecules involved in this signaling pathway were downregulated, suggesting its suppression in breast cancers. Activin-A expression correlates inversely with survival and metastasis in advanced breast cancers. Further, activin-A promotes anchorage-independent growth, epithelial-mesenchymal transition, invasion, angiogenesis, and stemness of breast cancer cells. We show that activin-A-induced phenotype is mediated by SMAD signaling pathway. In addition, activin-A expression affects the tumor-forming ability and metastatic colonization of cancer cells in nude mice. CONCLUSIONS:These results suggest that activin-A has a critical role in breast cancer progression and, hence, targeting this pathway can be a valuable strategy in treating breast cancer patients.

Project description:BackgroundHistone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy.MethodsTranscriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP-response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys-Asp-Glu-Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer-bearing mouse model was employed to analyze the effect of the HDAC3-KDELR2 axis on tumor growth.ResultsKDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT-PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo.ConclusionOur results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi-the endoplasmic reticulum traffic transport protein to HDAC-controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.

Project description:IntroductionExosomes are 30-100 nm membrane vesicles of endocytic origin, mediating diverse biological functions including tumor cell invasion, cell-cell communication and antigen presentation through transfer of proteins, mRNAs and microRNAs. Recent evidence suggests that microRNAs can be released through ceramide-dependent secretory machinery regulated by neutral sphingomyelinase 2 (nSMase2) enzyme encoded by the smpd3 gene that triggers exosome secretion. However, whether exosome-mediated microRNA transfer plays any role in cell invasion remains poorly understood. Thus, the aim of this study was to identify the exosomal microRNAs involved in breast cancer invasion.MethodsThe expression level of endogenous and exosomal miRNAs were examined by real time PCR and the expression level of target proteins were detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study its uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-10b was estimated by invasion assay.ResultsIn this study, we demonstrate that microRNA carrying exosomes can be transferred among different cell lines through direct uptake. miR-10b is highly expressed in metastatic breast cancer MDA-MB-231 cells as compared to non-metastatic breast cancer cells or non-malignant breast cells; it is actively secreted into medium via exosomes. In particular, nSMase2 or ceramide promotes the exosome-mediated miR-10b secretion whereas ceramide inhibitor suppresses this secretion. Moreover, upon uptake, miR-10b can suppress the protein level of its target genes such as HOXD10 and KLF4, indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could induce the invasion ability of non-malignant HMLE cells.ConclusionTogether, our results suggest that a set of specific microRNAs may play an important role in modulating tumor microenvironment through exosomes. Thus, a better understanding of this process may aid in the development of novel therapeutic agents.

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Activin A Promotes Regulatory T-cell-Mediated Immunosuppression in Irradiated Breast Cancer.

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