19 avrImmunogenic cell death its application in immunotherapeutic protocols19 avr 2013
Dr Jitka FUCIKOVA
Institut d'Immunology 2, Prague, République Tchèque
Invitée par Isabelle Cremer
Texte en anglais
Treatment of tumors by protocols based on combination of surgery, radiotherapy and systemic chemotherapy resulted in the improved prognosis of many human cancers. Despite the continuous introduction of new drugs and further improvements of chemotherapy protocols, it´s likely that at some point chemotherapy will reach its limits and clinical efficacy will plateau. Immunotherapy has emerged as another treatment modality with the potential to contribute to further improvements in the survival. The products of advanced cellular terapies must be generated using GMP-approved reagents and number of studies have addressed the need to generate large numbers of DCs for clinical trials according to regulatory authorities and to current legislation. The rising knowledge about dendritic cells (DCs) in the immune response against tumors and the ability to prepaire DCs in vitro leaded to the establishment of immunotherapy protocols. Breakthrough studies that identified markers of immunogenic tumor cell death after chemotherapy treatment challenge the long-time perception of chemotherapy and immunotherapy as opposing and incompatible treatment modalities.
Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In our study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell–loaded DCs efficiently stimulated tumor-specific IFN-g–producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells.
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