The Biodistribution and Immune Suppressive Effects of Breast Cancer–Derived Exosomes

Abstract

Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45 bone marrow-derived cells. Subsequent long-term conditioning of naïve mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer-derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816-27. ©2016 AACR.

Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use

“…Currently, the original research information on the biodistribution of EVs is extraordinarily scarce [83,84,85]. The use of clinically approved radioisotopes for labeling EVs seems a fruitful approach.…”

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Exosome derived tumor cells are called Tumor-Derived (TD) exosomes and accumulating evidence suggest that TD exosomes can construct a suitable TME to support tumor proliferation, angiogenesis, invasion and metastasis (Bobrie et al, 2012; Cho et al, 2012; King et al, 2012; Luga et al, 2012) through exosome mediated signaling. Breast cancer-derived exosomes can directly suppress T-cell proliferation and inhibit NK cell cytotoxicity, and thereby suppress the anticancer immune response in premetastatic organs (Wen et al, 2016). Studies show that the small GTPases RAB27A and RAB27B regulate exocytosis of multivesicular endosomes, which lead to exosome secretion, in human HeLa cells.…”

Biological Functions and Current Advances in Isolation and Detection Strategies for Exosome Nanovesicles

“…It has also been reported that exosomes, along with cytokines and other soluble mediators, are involved in the transport of bone marrow‐derived cells to a premetastatic niche to enable the establishment of a tumor microenvironment . Furthermore, exosomes were also found to maintain a role in tumor survival via allowing the tumors to design an immune‐escape mechanism …”