Citations

Exosomes are membrane-enveloped nanosized (30–150 nm) extracellular vesicles of endosomal origin produced by almost all cell types and encompass a multitude of functioning biomolecules. Exosomes have been considered crucial players of cell-to-cell communication in physiological and pathological conditions. Accumulating evidence suggests that exosomes can modulate the immune system by delivering a plethora of signals that can either stimulate or suppress immune responses, which have potential applications as immunotherapies for cancer and autoimmune diseases. Here, we discuss the current knowledge about the active biomolecular components of exosomes that contribute to exosomal function in modulating different immune cells and also how these immune cell-derived exosomes play critical roles in immune responses. We further discuss the translational potential of engineered exosomes as immunotherapeutic agents with their advantages over conventional nanocarriers for drug delivery and ongoing clinical trials.

Abstract Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259–70. ©2016 AACR.