High hydrostatic pressure induces immunogenic cell death in human tumor cells

摘要

Recent studies have identified molecular events characteristic of immunogenic cell death (ICD), including surface exposure of calreticulin (CRT), the heat shock proteins HSP70 and HSP90, the release of high-mobility group box protein 1 (HMGB1) and the release of ATP from dying cells. We investigated the potential of high hydrostatic pressure (HHP) to induce ICD in human tumor cells. HHP induced the rapid expression of HSP70, HSP90 and CRT on the cell surface. HHP also induced the release of HMGB1 and ATP. The interaction of dendritic cells (DCs) with HHP-treated tumor cells led to a more rapid rate of DC phagocytosis, upregulation of CD83, CD86 and HLA-DR and the release of interleukin IL-6, IL-12p70 and TNF-α. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific T cells. DCs pulsed with HHP-treated tumor cells also induced the lowest number of regulatory T cells. In addition, we found that the key features of the endoplasmic reticulum stress-mediated apoptotic pathway, such as reactive oxygen species production, phosphorylation of the translation initiation factor eIF2α and activation of caspase-8, were activated by HHP treatment. Therefore, HHP acts as a reliable and potent inducer of ICD in human tumor cells. What's new? Some cytotoxic agents used in cancer treatment activate an immunogenic form of apoptosis, which causes the dying tumor cells to induce an effective antitumor immune response. Here, the authors find that exposure to high hydrostatic pressure (HHP) induces bona fide immunogenic cell death in a wide range of human tumor cell lines and primary tumor cells. As HHP treatment is relatively easily standardized under good manufacturing practices conditions, the authors initiated multiple clinical trials evaluating the potential of dendritic cells loaded with HHP-treated cancer cells to induce tumor cell-specific immune responses in patients with prostate cancer.