Abstract

Exosomes are small membrane vesicles secreted in the extracellular medium by various cell types, including tumor and immune cells. They are produced inside the cells in endocytic multivesicular compartments, and released when these compartments fuse with the plasma membrane. Exosomes purified in vitro from tumor cell lines have been shown to modulate immune responses in various ways, inhibiting or enhancing them, depending on the experimental systems used. In vivo, exosomes or vesicles bearing tumor markers have been found in the serum of cancer patients or tumor-bearing mice, but the role played by such tumor-derived exosomes in vivo remains unclear. To answer this question, our approach is to identify intracellular molecules specifically involved in the exosome secretion machinery. Using a library of shRNA, we have recently shown a crucial role of two small Rab GTPases in exosome secretion by the human HeLa tumor cell line. We are now using tools to inhibit these particular Rabs in mouse tumor cells, in order to determine whether (1) the molecular machinery involved in exosome secretion is conserved in different human and mouse cell types, and (2) how inhibiting specifically the secretion of exosomes by tumor cells affects growth and immune responses generated in vivo by these tumors.