Extracellular vesicles (EVs) are secreted by almost all cells. They contain proteins, lipids, and nucleic acids which are delivered from the parent cells to the recipient cells. Thereby, they function as mediators of intercellular communication and molecular transfer. Recent evidences suggest that exosomes, a small subset of EVs, are involved in numerous physiological and pathological processes and play essential roles in remodeling the tumor immune microenvironment even before the occurrence and metastasis of cancer. Exosomes derived from tumor cells and host cells mediate their mutual regulation locally or remotely, thereby determining the responsiveness of cancer therapies. As such, tumor‐derived circulating exosomes are considered as noninvasive biomarkers for early detection and diagnosis of tumor. Exosome‐based therapies are also emerging as cutting‐edge and promising strategies that could be applied to suppress tumor progression or enhance anti‐tumor immunity. Herein, the current understanding of exosomes and their key roles in modulating immune responses, as well as their potential therapeutic applications are outlined. The limitations of current studies are also presented and directions for future research are described.

TGF-β is pro-metastatic for the late-stage breast cancer cells. Despite recent progress, the regulation of TGF-β type II receptor remains uncertain. Here we report that FAF1 destabilizes TβRII on the cell surface by recruiting the VCP/E3 ligase complex, thereby limiting excessive TGF-β response. Importantly, activated AKT directly phosphorylates FAF1 at Ser 582, which disrupts the FAF1–VCP complex and reduces FAF1 at the plasma membrane. The latter results in an increase in TβRII at the cell surface that promotes both TGF-β-induced SMAD and non-SMAD signalling. We uncover a metastasis suppressing role for FAF1 through analyses of FAF1-knockout animals, various in vitro and in vivo models of epithelial-to-mesenchymal transition and metastasis, an MMTV-PyMT transgenic mouse model of mammary tumour progression and clinical breast cancer samples. These findings describe a previously uncharacterized mechanism by which TβRII is tightly controlled. Together, we reveal how SMAD and AKT pathways interact to confer pro-oncogenic responses to TGF-β.

Cancer immunotherapies have shown clinical success in various types of tumors but the patient response rate is low, particularly in breast cancer. Here we report that malignant breast cancer cells can transfer active TGF-β type II receptor (TβRII) via tumor-derived extracellular vesicles (TEV) and thereby stimulate TGF-β signaling in recipient cells. Up-take of extracellular vesicle-TβRII (EV-TβRII) in low-grade tumor cells initiates epithelial-to-mesenchymal transition (EMT), thus reinforcing cancer stemness and increasing metastasis in intracardial xenograft and orthotopic transplantation models. EV-TβRII delivered as cargo to CD8+ T cells induces the activation of SMAD3 which we demonstrated to associate and cooperate with TCF1 transcription factor to impose CD8+ T cell exhaustion, resulting in failure of immunotherapy. The levels of TβRII+ circulating extracellular vesicles (crEV) appears to correlate with tumor burden, metastasis and patient survival, thereby serve as a non-invasive screening tool to detect malignant breast tumor stages. Thus, our findings not only identify a possible mechanism by which breast cancer cells can promote T cell exhaustion and dampen host anti-tumor immunity, but may also identify a target for immune therapy against the most devastating breast tumors.

Exo-OH on ISB has long been asserted as a highly reactive moiety compared with endo-OH. Herein, we report that the nucleophilic attack surmounts steric hindrance in rendering endo-OH more reactive than exo-OH in case of transesterification with DPC.

We previously devised a cucumber mosaic virus (CMV)-based vector system carrying microRNA target mimic sequences for analysis of microRNA function in Arabidopsis thaliana. We describe an improved version in which target mimic cloning is achieved by annealing two partly-overlapping complementary DNA oligonucleotides for insertion into an infectious clone of CMV RNA3 (LS strain) fused to the cauliflower mosaic virus-derived 35S promoter. LS-CMV variants carrying mimic sequences were generated by co-infiltrating plants with Agrobacterium tumefaciens cells harboring engineered RNA3 with cells carrying RNA1 and RNA2 infectious clones. The utility of using agroinfection to deliver LS-CMV-derived microRNA target mimic sequences was demonstrated using a miR165/166 target mimic and three solanaceous hosts: Nicotiana benthamiana, tobacco (N. tabacum), and tomato (Solanum lycopersicum). In all three hosts the miR165/166 target mimic induced marked changes in developmental phenotype. Inhibition of miRNA accumulation and increased target mRNA (HD-ZIP III) accumulation was demonstrated in tomato. Thus, a CMV-derived target mimic delivered via agroinfection is a simple, cheap and powerful means of launching virus-based miRNA mimics and is likely to be useful for high-throughput investigation of miRNA function in a wide range of plants.