MAP kinase kinase 1 (MEK1) within extracellular vesicles inhibits tumour growth by promoting anti-tumour immunity.

Extracellular vesicles (EVs) mediate intercellular communication in many physiologic processes and can modulate immune responses in individuals with cancer. Most studies of EVs in cancer have focused on their tumour promoting properties. Whether and how EVs might mediate tumour regression besides carrying antigens has not been well characterized.

Delivery of miR-214 via extracellular vesicles downregulates expression and pro-inflammatory cytokine genes in macrophages.

Aim: Tumor-infiltrating macrophages are tumor-promoting and show activation of the unfolded protein response (UPR). The transcription factor X-box binding protein 1 (XBP1) is a conserved element of the UPR. Upon activation, the UPR mediates the transcriptional activation of pro-inflammatory cytokines and immune suppressive factors, hence contributing to immune dysregulation in the tumor microenvironment (TME).

Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing.

The PD-1:PD-L1 axis is a binary interaction that delivers inhibitory signals to T cells, impeding both immune surveillance and response to immunotherapy. Here we analyzed a phenomenon whereby tumor-specific T cells induce PD-L1 upregulation in autologous MDS cells in short-term culture, through a mechanism that is cell-contact-independent and partially IFNγ-dependent. After investigating a panel of small-molecule inhibitors, we determined that PD-L1 upregulation was attributed to the PKR-like ER kinase (PERK) branch of the unfolded protein response.

Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue.

Targeting the delivery of therapeutics specifically to diseased tissue enhances their efficacy and decreases their side effects. Here we show that mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation following the genetic modification of the cells for their display of chemoattractant receptors and endothelial-cell-binding molecules are effective vehicles for the targeted delivery of therapeutics. The enucleated cells neither proliferate nor permanently engraft in the host, yet retain the organelles for energy and protein production, undergo integrin-regulated adhesion to inflamed endothelial cells, and actively home to chemokine gradients established by diseased tissues.

The unfolded protein response links tumor aneuploidy to local immune dysregulation.

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages.