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High hydrostatic pressure to induce immunogenic cell death in human tumor cells.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Recent studies have identified molecular events characteristic of immunogenic cell death. These include surface exposure of calreticulin, HSP70 and HSP90, release of intranuclear HMGB1 and secretion of ATP from dying cells. Several chemotherapeutic agents, including anthracyclins, oxaliplatin and bortezomib, and hypericin-based photodynamic therapy have been described to induce the immunogenic cell death in human tumor cells. We investigated the potential of high hydrostatic pressure (HHP) to induce immunogenic cell death in human tumor cells. Methods: Prostate and ovarian cancer cell lines and primary tumor cells were treated by HHP and we analyzed the kinetics of the expression of immunogenic cell death markers. HHP killed tumor cells expressing immunogenic cell death markers were tested for their ability to activate dendritic cells (DCs), to induce tumor specific T cells and regulatory T cells. Results: HHP induced rapid expression of HSP70, HSP90 and calreticulin on the cell surface of all tested cell lines and primary tumor cells. HHP also induced release of HMGB1 and ATP from treated cells. The kinetics of expression was similar to doxorubicin, HHP, however, induced 1.5-2 fold higher expression of HSP70, HSP90 and calreticulin. The interaction of DCs with HHP-treated tumor cells led to the faster rate of phagocytosis, significant upregulation of CD83, CD86 and HLA-DR and release of IL-6, IL-12p70 and TNFα. The ability of HHP-killed tumor cells to promote DCs maturation was cell contact dependent. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific CD4+ and CD8+IFN-g-producing T cells even in the absence of additional maturation stimulus. DCs pulsed with HHP treated tumor cells also induced the lowest number of regulatory T cells among the tested conditions. Cells treated by HHP can by cryopreserved in liquid nitrogen and retain their immunogenic properties upon thawing thus allowing for their convenient use in the manufacturing of cancer immunotherapy products. Conclusions: High hydrostatic pressure is a reliable and very potent inducer of immunogenic cell death in the wide range of human tumor cell lines and primary tumor cells.