title: Low dose of GRP78-targeting subtilase cytotoxin improves the efficacy of photodynamic therapy in vivo.
abstract: Photodynamic therapy (PDT) exerts direct cytotoxic effects on tumor cells, destroys tumor blood and lymphatic vessels and induces local inflammation. Although PDT triggers the release of immunogenic antigens from tumor cells, the degree of immune stimulation is regimen-dependent. The highest immunogenicity is achieved at sub-lethal doses, which at the same time trigger cytoprotective responses, that include increased expression of glucose-regulated protein 78 (GRP78). To mitigate the cytoprotective effects of GRP78 and preserve the immunoregulatory activity of PDT, we investigated the in vivo efficacy of PDT in combination with EGF-SubA cytotoxin that was shown to potentiate in vitro PDT cytotoxicity by inactivating GRP78. Treatment of immunocompetent BALB/c mice with EGF-SubA improved the efficacy of PDT but only when mice were treated with a dose of EGF-SubA that exerted less pronounced effects on the number of T and B lymphocytes as well as dendritic cells in mouse spleens. The observed antitumor effects were critically dependent on CD8+ T cells and were completely abrogated in immunodeficient SCID mice. All these results suggest that GRP78 targeting improves in vivo PDT efficacy provided intact T-cell immune system.
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gabrysiak
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wachowska
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Barankiewicz
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Pilch
authors.affiliation: Department of Pathology, Center of Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ratajska
authors.affiliation: Department of Pathology, Center of Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Skrzypek
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Winiarska
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Antoni
authors.initials: A
authors.lastname: Domagala
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Rygiel
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kracow, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.affiliation: EPIRUS Biopharmaceuticals Netherlands BV, 3584 CM Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Firczuk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D017323:Dihematoporphyrin Ether / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004815:Epidermal Growth Factor / Q000008:administration & dosage*; D029968:Escherichia coli Proteins / Q000008:administration & dosage*; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013381:Subtilisins / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D017319:Photosensitizing Agents; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D017323:Dihematoporphyrin Ether; D013381:Subtilisins; C527234:subtilase cytotoxin, E coli