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Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin).

ABSTRACT: Both the pre-apoptotic exposure to calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death. Photodynamic therapy (PDT) uses non-toxic photosensitizers and visible light at a specific wavelength in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumor microvasculature, and stimulate the host immune system. We have previously shown that glycoconjugated chlorin (G-chlorin) has superior cancer cell selectivity and effectively suppresses the growth of xenograft tumors. In the present study, we evaluated the immunogenicity of PDT with G-chlorin treatment in colon cancer cells. PDT with G-chlorin suppressed CT26 (mouse colon cancer cells) tumor growth considerably more efficiently in immunocompetent mice (wild-type mice, allograft model) than in immune-deficient mice (nude mice, xenograft model), although control treatments were not different between the two. This treatment also induced CRT translocation and HMGB1 release in cells, as shown by western blot and immunofluorescence staining. To evaluate the use of PDT-treated cells as a tumor vaccine, we employed a syngeneic mouse tumor model (allograft model). Mice inoculated with PDT-treated CT26 cells were significantly protected against a subsequent challenge with live CT26 cells, and this protection was inhibited by siRNA for CRT or HMGB1. In conclusion, PDT with G-chlorin treatment induced immunogenic cell death in a mouse model, where the immunogenicity of this treatment was directed by CRT expression and HMGB1 release.

SUBMITTER: Tanaka M

PROVIDER: S-EPMC5216938 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin).

Tanaka Mamoru M Kataoka Hiromi H Yano Shigenobu S Sawada Takuya T Akashi Haruo H Inoue Masahiro M Suzuki Shugo S Inagaki Yusuke Y Hayashi Noriyuki N Nishie Hirotada H Shimura Takaya T Mizoshita Tsutomu T Mori Yoshinori Y Kubota Eiji E Tanida Satoshi S Takahashi Satoru S Joh Takashi T

Oncotarget 20160701 30

Both the pre-apoptotic exposure to calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death. Photodynamic therapy (PDT) uses non-toxic photosensitizers and visible light at a specific wavelength in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumor microvasculature, and stimulate the host immune system. We have previously show ...[more]

PMID: 27363018

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Project description:BackgroundAnti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). Therefore, when developing new treatment strategies, it is extremely important to choose methods that induce ICD and thereby activate anti-tumor immune response leading to the most effective destruction of tumor cells. The aim of this work was to analyze whether the clinically widely used photosensitizers, photosens (PS) and photodithazine (PD), can induce ICD when used in photodynamic therapy (PDT).MethodsCell death in murine glioma GL261 or fibrosarcoma MCA205 cells was induced by PS- or PD-PDT and cell death was analyzed by MTT or flow cytometry. Intracellular distribution of PS and PD was studied by using the laser scanning microscope. Calreticulin exposure and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of dying cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and maturation (CD11c+CD86+, CD11c+CD40+) of BMDCs and production of IL-6 in the supernatant were measured. In vivo immunogenicity was analyzed in mouse tumor prophylactic vaccination model.ResultsWe determined the optimal concentrations of the photosensitizers and found that at a light dose of 20 J/cm2 (λex 615-635 nm) both PS and PD efficiently induced cell death in glioma GL261 and fibrosarcoma MCA205 cells. We demonstrate that PS localized predominantly in the lysosomes and that the cell death induced by PS-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) and by ferrostatin-1 and DFO (ferroptosis inhibitors), but not by the necroptosis inhibitor necrostatin-1 s. By contrast, PD accumulated in the endoplasmic reticulum and Golgi apparatus, and the cell death induced by PD-PDT was inhibited only by z-VAD-fmk. Dying cancer cells induced by PS-PDT or PD-PDT emit calreticulin, HMGB1 and ATP and they were efficiently engulfed by BMDCs, which then matured, became activated and produced IL-6. Using dying cancer cells induced by PS-PDT or PD-PDT, we demonstrate the efficient vaccination potential of ICD in vivo.ConclusionsAltogether, these results identify PS and PD as novel ICD inducers that could be effectively combined with PDT in cancer therapy.

Project description:Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we induced ICD in colorectal cancer (CRC) cell lines in vitro and in vivo by targeting the 18 kDa translocator protein (TSPO), a mitochondrial receptor overexpressed in CRC. Photodynamic therapy (PDT) using a TSPO-targeted photosensitizer, IR700DX-6T, caused effective apoptotic cell death in fourteen CRC cell lines. In a syngeneic immunocompetent CRC mouse model, the growth of tumors subjected to TSPO-PDT was greatly suppressed. Remarkably, untreated tumors in the opposing flank also showed marked growth suppression. Dendritic and CD8+ T cells were activated after TSPO-PDT treatment, accompanied by decreased Treg cells in both treated and non-treated tumors. In addition, a cancer vaccine developed from TSPO-PDT produced a significant tumor inhibition effect. These results indicate that TSPO-PDT could not only directly suppress tumor growth but also dramatically provoke host anti-tumor immunity, highlighting the potential of TSPO-PDT as a successful therapeutic for CRC that exhibits systemic effects. STATEMENT OF SIGNIFICANCE: Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we report a new therapeutic approach that can reduce the growth of multiple CRC cell lines by inducing ICD. Notably, a direct and abscopal effect was observed in mouse tumor-derived MC38 cells when injected into syngeneic immunocompetent mice. If comparable effects could be achieved in humans, it would establish a novel paradigm for treating micro- and macro-metastasis.

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Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin).

Publications

Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin).

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