Exosomes drive anticancer immunosuppression - the last paragraph, in bold, emphasizes the role of exosomes in immunosuppression. It would be difficult to develop different drugs targeting all the possible exosomes - but having the Hemo Purifier to take care of all of them would be much more economical.
25 Jan 2010
Myeloid-derived suppressor cells (MDSCs) are immature immune cells with the ability to suppress T-cell activation. This cell population accumulates in patients with tumours and is a major suppressor of antitumour immunity. Exosomes produced by tumour cells contain T-cell activating antigens as well as having immunosuppressive powers. New research has identified a mechanism by which exosomes promote immunosuppression through the activation of MDSCs with the heat shock protein, Hsp72.
Myeloid-derived suppressor cells are a population of immature myeloid cells, which in humans are characterised by their CD11b+CD33+HLA-DR– nature. In humans and mice with tumours this cell population is enlarged, and activated MDSCs are able to induce antigen-specific MHC class I-restricted tolerance. This is in contrast to naïve cells which lack immunosuppressive properties, suggesting that MDSCs require activation signals from tumour cells to support their suppressive function.
Tumour induced MDSC activation and expansion is known to be regulated by soluble factors, such as Stat3, but also by microvesicles – exosomes. Exosomes are endosome-derived organelles which are secreted through exocytosis and are used for intracellular crosstalk and receptor release in both normal and pathologic conditions. Tumour-derived exosomes were initially described as being immunostimulatory due to their containing T-cell stimulating tumour antigens, but recent reports have suggested that they may have a role in immunosuppression via inhibiting T-cell function.
A study by researchers in Dijon, France published online in the Journal of Clinical Investigation has identified a mechanism by which tumour-derived exosomes can promote MDSC immunosuppression. They found that Stat3, a transcription factor known to promote tumour cell survival, was activated in MDSCs in response to tumour-derived exosomes. The activation of Stat3 promoted the immunosuppressive function of MDSCs without triggering population expansion. The authors found that tumour-derived exosomes express Hsp72, a major heat shock protein known to inhibit apoptosis. Hsp72 is also a ligand for TLR2, and exposure of MDSCs to Hsp72 on exosomes leads to TLR2/MyD88 dependent signalling resulting in production of IL-6, a well known activator of Stat3. Importantly they found that decreasing tumour exosome release pharmacologically in vivo, with inhibitors, in mice enhanced the efficacy of the chemotherapeutic drug cyclophosphamide.
The work indicates that tumour induced immunosuppression depends partly on the tumours ability to induce functional MDSCs by releasing Hsp72-expressing exosomes. The work suggests that drugs that interfere with exosome release may enhance the efficacy of current chemotherapy agents.
Reference
F Chalmin, S Ladoire, G Mignot, J Vincent, M Bruchard, J-P Remy-Martin, W Boireau, A Rouleau, B Simon, D Lanneau, A De Thonel, G Multhoff, A Hamman, F Martin, B Chauffert, E Solary, L Zitvogel, C Garrido, B Ryffel, C Borg, L Apetoh, C Rébé, F Ghiringhelli (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clinical Investigation Online Early
