Dataset Information

Targeting immunosuppression by TGF-β1 for cancer immunotherapy.

ABSTRACT: The TGF-β1 cytokine is a key mediator of many biological processes. Complex regulatory mechanisms are in place that allow one single molecule to exert so many distinct indispensable activities. The complexity of TGF-β1 biology is further illustrated by the opposing dual roles it plays during cancer progression. Risks of toxicities combined with lack of convincing therapeutical efficacy explain at least in part why therapies targeting TGF-β1 have lagged behind in past decades. However, recent successes of immunostimulatory antibodies for the immunotherapy of cancer and findings that TGF-β1 activity associates with resistance to immunotherapeutic drugs have revived the field. In this review, we discuss the biology of TGF-β1 with a special focus on its roles in regulating immune responses in the context of cancer. We describe the various therapeutic approaches available to inhibit TGF-β signalling, and more recent findings that allow selective targeting of specific sources of TGF-β activity, which may prove relevant to increase the efficacy and reduce the toxicity of cancer immunotherapy.

SUBMITTER: de Streel G

PROVIDER: S-EPMC8484859 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting immunosuppression by TGF-β1 for cancer immunotherapy.

de Streel Grégoire G Lucas Sophie S

Biochemical pharmacology 20210722

The TGF-β1 cytokine is a key mediator of many biological processes. Complex regulatory mechanisms are in place that allow one single molecule to exert so many distinct indispensable activities. The complexity of TGF-β1 biology is further illustrated by the opposing dual roles it plays during cancer progression. Risks of toxicities combined with lack of convincing therapeutical efficacy explain at least in part why therapies targeting TGF-β1 have lagged behind in past decades. However, recent suc ...[more]

PMID: 34302795

Similar Datasets

Project description:BackgroundHoneysuckle is a time-honored herb with anticancer activity in traditional Chinese medicine. Recently, accumulating reports are suggesting that the microRNAs in this medicinal plant not only play a physiological role in their original system, but also can be transmitted to another species as potential therapeutic components. In the numerous bioactive investigations, the anti-tumor effects of these microRNAs in the magical herb are rarely studied, especially the special miR2911, a honeysuckle-encoded atypical microRNA, with high stability during the boiling process and unique biological activity to target TGF-β1 mRNA.MethodsLuciferase assay was conducted to test the ability of miR2911 to target TGF-β1 mRNA. ELISA was performed to determine the expression level of TGF-β1 of mouse colorectal adenocarcinoma CT26 cells when treated with miR2911 and tumor tissue in Sidt1+/+ and Sidt1-/- mice. qRT-PCR was performed to examine the level of expression of miR2911. Tumor-bearing wild and nude mice were employed to evaluate the anti-tumor effect of honeysuckle and miR2911 in vivo. Tumor tissue necrosis was observed by H&E staining. Besides, the infiltration of T lymphocytes across solid tumors was tested by immunostaining staining.ResultsOur results showed that honeysuckle slowed the development of colon cancer down. Further research showed that miR2911 could bind strongly to TGF-β1 mRNA and down-regulate the expression of TGF-β1 and had a high stability under boiling and acid condition. Moreover, SIDT1 mediated dietary miR2911 inter-species absorption. And we found that miR2911 had a similar anticancer effect as honeysuckle. Mechanistically, miR2911 reversed the tumor-promoting effect of TGF-β1 by an increase of T lymphocytes infiltration, resulting in slowing the colon cancer process in immunocompetent mice. Consistent with this inference, the anti-tumor effect of miR2911 was revealed to be abolished in T cell immune deficiency mice.ConclusionTaken together, honeysuckle-derived miR2911 showed an anti-tumor effect in colon cancer through targeting TGF-β1 mRNA. The down-regulation of TGF-β1 promoted T lymphocytes infiltration, and accordingly impeded the colon tumor development.

Project description:Transforming growth factor (TGF)‑β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor‑derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF‑β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF‑β1 stimulated cervical cancer cells to secrete more miR‑663b‑containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR‑663b directly targets the 3'-untranslated regions (3'‑UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial‑mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR‑663b, causing increased expression of epithelial differentiation marker E‑cadherin and decreased expression of mesenchymal markers N‑cadherin and β‑catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR‑663b. Exosome PKH67‑labeling experiment verified that exosomal miR‑663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR‑663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real‑time transcription‑polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell‑derived exosomal miR‑663b is endocytosed by cervical cancer cells adjacent or distant after TGF‑β1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

Dataset Information

Targeting immunosuppression by TGF-β1 for cancer immunotherapy.

Publications

Targeting immunosuppression by TGF-β1 for cancer immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets