Alveolar macrophage secretion of vesicular SOCS3 represents a platform for lung cancer therapeutics.

Lung cancer remains the leading cause of cancer-related death in the United States. Although the alveolar macrophage (AM) comprises the major resident immune cell in the lung, few studies have investigated its role in lung cancer development. We recently discovered a potentially novel mechanism wherein AMs regulate STAT-induced inflammatory responses in neighboring epithelial cells (ECs) via secretion and delivery of suppressors of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs).

Phosphatidylinositol 4-phosphate is a major source of GPCR-stimulated phosphoinositide production.

Phospholipase C (PLC) enzymes hydrolyze the plasma membrane (PM) lipid phosphatidylinositol 4,5-bisphosphate (PI4,5P) to generate the second messengers inositol trisphosphate (IP) and diacylglycerol (DAG) in response to receptor activation in almost all mammalian cells. We previously found that stimulation of G protein-coupled receptors (GPCRs) in cardiac cells leads to the PLC-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) at the Golgi, a process required for the activation of nuclear protein kinase D (PKD) during cardiac hypertrophy. We hypothesized that GPCR-stimulated PLC activation leading to direct PI4P hydrolysis may be a general mechanism for DAG production.

Targeted calcium influx boosts cytotoxic T lymphocyte function in the tumour microenvironment.

Adoptive cell transfer utilizing tumour-targeting cytotoxic T lymphocytes (CTLs) is one of the most effective immunotherapies against haematological malignancies, but significant clinical success has not yet been achieved in solid tumours due in part to the strong immunosuppressive tumour microenvironment. Here, we show that suppression of CTL killing by CD4CD25Foxp3 regulatory T cell (Treg) is in part mediated by TGFβ-induced inhibition of inositol trisphosphate (IP) production, leading to a decrease in T cell receptor (TCR)-dependent intracellular Ca response. Highly selective optical control of Ca signalling in adoptively transferred CTLs enhances T cell activation and IFN-γ production in vitro, leading to a significant reduction in tumour growth in mice.