In Vitro And In Vivo Inhibition Of T Cell Responses By Exosomes Prepared From Tumor Tissues

Immunological surveillance was firstly proposed by Burnet and Thomas. According to the concept, the immune system can prevent host from neoplasm development. However, tumors often occur through escaping immunological surveillance successfully. What are their tricks? By far, immune mechanisms by which tumors escape immunological surveillance may be related to two respects: 1) mechanisms related with tumor-induced dysfunction of tumor-bearing host immune system; 2) mechanisms associated with the variants of tumor cells themselves that aim to inhibit the activation of the immune system. Tumor variants lose some phenotypes which are important for the successful induction of immune responses (like MHC-I) or express some proteins that promote tumor cell outgrowth and inhibit tumor cell apoptosis.Cells of the immune system taking part in tumor-host interaction include T cells, natural killer cells (NK cells) and antigen-presenting cells (APC, such as dendritic cells, B cells, macrophages). The direct interplay between tumor cells and immune cells could inhibit the immunostimulatory function of dendritic cells (DC).More interestingly, tumor cells or tumor tissue could release inhibitors of lymphocyte activation. These inhibitors secreted into supernatants could inhibit LPS-induced proliferation of B cells and PHA-induced proliferation of T cells and allogeneic MLR. Several kinds of factors associated with immunosuppressive functions by tumor cells had been detected in tumor culture supernatant, such as TGF-P, IL-10, VEGF. Immunosuppressive cytokines affect lymphocyte responses, angiogenesis, and even tumor growth. Most of them were reported to be soluble. However, more attractive, melanoma cells secreted FasL-bearing microvesicles and FasL was inlayed on these vesicles inducing lymphocyte apoptosis, indicating tumor cells can release microvesicles which can inhibit immune response, thus contributing to immune escape of tumor cells.Exosomes are a kind of membrane vesicles about 30-90nm and initially described in culture media of some normal and neoplastic cell lines and purified fromreticulocytes culture supernatant firstly. By far, exosomes can be secreted by most of cells in culture, such as reticulocytes, platelets, B lymphocytes, cytotoxic T lymphocytes, DC, mast cells, and some tumor cells. The biological functions of exosomes are still not fully understood, although some data have been got on the biological functions of exosomes as following. Firstly, exosomes might play a role in discarding wastes such as TfRs in reticulocytes. Secondly, exosomes might serve as media in membrane exchange between cells or handle intercellular signaling. Thirdly, exosomes may serve as APCs to stimulate lymphocytes. Finally, exosomes may be correlated with retroviral transmission. One question is proposed that the biological functions of exosomes are just so much?Exosomes can serve as immune protective vesicles. In 1998, Laurence Zitvogel et al. reported that exosomes derived from DC could eradicate the established murine tumor. Encouraged by such exciting findings, scientists started to focus on the potential tumor vaccine of exosomes. And these researches suggested that exosomes derived from DCs or DCs pulsed with tumor cell- derived exosomes can serve as cancer vaccines, and DCs were shown to be essential in the induction of antitumor immune response by this approach. Up to now, clinical trails have been conducted in U.S.A. and Europe to observe the antitumor effects of exosomes. Exosomes may be a kind of potential vaccines for tumors in future.On the other hand, exosomes may be a kind of tolerogenic materials. Exosomes derived from human intestinal epithelial cell (IEC) could be released from apical and basolateral sides and expressed MHC class I molecules, CD26, CD63 in basal conditions besides MHC class II in inflammatory conditions. The data showed exosomes might be a mechanism of oral tolerance. Exosome-like vesicles isolated from rat IEC line, which were pulsed by antigens, were shown to induce antigen-spec...