Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure induce strong immune responses and display therapeutic effects both in murine TC-1 and TRAMP-C2 tumors when combined with docetaxel chemotherapy

Abstract

High hydrostatic pressure (HHP) has been shown to induce immunogenic cell death of cancer cells, facilitating their uptake by dendritic cells (DC) and subsequent presentation of tumor antigens. In the present study, we demonstrated immunogenicity of the HHP-treated tumor cells in mice. HHP was able to induce immunogenic cell death of both TC-1 and TRAMP-C2 tumor cells, representing murine models for human papilloma virus-associated tumors and prostate cancer, respectively. HHP-treated cells induced stronger immune responses in mice immunized with these tumor cells, documented by higher spleen cell cytotoxicity and increased IFNγ production as compared to irradiated tumor cells, accompanied by suppression of tumor growth in vivo in the case of TC-1 tumors, but not TRAMP-C2 tumors. Furthermore, HHP-treated cells were used for DC-based vaccine antigen pulsing. DC co-cultured with HHP-treated tumor cells and matured by a TLR 9 agonist exhibited higher cell surface expression of maturation markers and production of IL-12 and other cytokines, as compared to the DC pulsed with irradiated tumor cells. Immunization with DC cell-based vaccines pulsed with HHP-treated tumor cells induced high immune responses, detected by increased spleen cell cytotoxicity and elevated IFNγ production. The DC-based vaccine pulsed with HHP-treated tumor cells combined with docetaxel chemotherapy significantly inhibited growth of both TC-1 and TRAMP-C2 tumors. Our results indicate that DC-based vaccines pulsed with HHP-inactivated tumor cells can be a suitable tool for chemoimmunotherapy, particularly with regard to the findings that poorly immunogenic TRAMP-C2 tumors were susceptible to this treatment modality.

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…In this regimen, DC-based vaccines were administered after the tumor challenge at regular intervals between docetaxel administrations. The tumor inhibitory effect of both immunogenic and weakly immunogenic models resulted in more effective suppression of growth, when compared with the untreated tumor-bearing animals [138]. A similar outcome was reported when the DC-based vaccines pulsed with HHP-treated tumor cells was combined with the chemotherapeutic cyclophosphamide [140].…”

“…Moreover, DCs that were loaded with HHP-treated tumor cells exhibited an upregulation of maturation markers, chemotactic migration, and the release of pro-inflammatory interleukins when compared to unloaded DCs. In addition, HHP-treated tumor lysate loaded-DCs were able to activate tumor-specific T cells while also downregulating the number of Treg [137][138][139][140].…”

“…Preliminary results have demonstrated that apoptosis induction by HHP was accompanied by exposure/release of several immunogenic molecules, such as HSP90, HSP70, CRT, ATP, and HMGB1, in human prostate, leukemia, and ovarian tumor cell lines and/or primary tumor cells [137,138]. For that reason, the use of HHP-killed human tumor cells has been tested for DC-based vaccine generation [137][138][139][140]. In these assays, human mo-DCs were co-cultured at a DC/tumor cell ratio of 5:1 with cancer cells that were previously subjected to lethal doses of HHP, and then incubated with poly(I:C) or LPS as maturation stimuli.…”

Immunomodulation by ionizing radiation—impact for design of radio‐immunotherapies and for treatment of inflammatory diseases

“…Spisek and colleagues also demonstrated that human ovarian and prostate tumor cells can be rendered immunogenic by HHP‐treatment and that DCs pulsed with HHP‐killed tumor cells induced tumor‐specific T cells . Combination of HHP‐vaccines with CT was efficient in inducing strong anti‐tumor immune responses . We observed in the murine B16 melanoma model that autologous HHP‐vaccine acts synergistically with RT to retard tumor growth (C. Seitz et al, unpublished data).…”

“…161 Combination of HHP-vaccines with CT was efficient in inducing strong anti-tumor immune responses. 162 We observed in the murine B16 melanoma model that autologous HHP-vaccine acts synergistically with RT to retard tumor growth (C. Seitz et al, unpublished data). HHP treatment of selected human cancer cell lines leads to degradation of tumor antigens.…”