title: 5-Aza-2'-deoxycytidine potentiates antitumour immune response induced by photodynamic therapy.
abstract: Photodynamic therapy (PDT) of tumours is based on administration of a photosensitiser followed by irradiation of the tumour with visible light leading to production of reactive oxygen species that cause direct tumour cell death and vascular damage. PDT also initiates acute local inflammation, which facilitates the development of adaptive antitumour immunity. It has recently been reported that PDT can induce strong antitumour immunity towards tumours cells expressing P1A, tumour-associated antigen. Using four different tumour models, we show that antitumour immune response can be further improved when PDT is combined with a clinically approved epigenetic agent that induces expression of a silenced P1A antigen. Induction of P1A with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor, resulted in potentiated antitumour effects in mice with Lewis lung carcinoma and 4T1 mammary carcinoma when combined with PDT treatment. In CT26 colon carcinoma and EMT6 mammary carcinoma models the combination therapy resulted in complete responses and long-term survival. All long-term surviving mice were resistant to re-inoculation with the same tumour cells. Antitumour efficacy of the combination treatment was severely impaired by depletion of CD8(+) cytotoxic T cells, whereas adoptive transfer of CD8(+) T cells from long-term surviving mice allowed for significant tumour growth delay in tumour-bearing mice. Taken together, these findings show that PDT leads to strong specific antitumour immune responses, and that epigenetic modification of tumour antigens levels may be a novel approach to further enhance the effectiveness of PDT. The present results provide a strong rationale for clinical development of this therapeutic approach.
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: 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: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Weronika
authors.initials: W
authors.lastname: Bednarek
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: Tomasz
authors.initials: T
authors.lastname: Rygiel
authors.affiliation: Bioceros, Yalelaan 46, Alexander Numan Building, 2nd floor, 3584 CM Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA, USA; Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Mroz
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland. Electronic address: jakub.golab@wum.edu.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D000077209:Decitabine; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010778:Photochemotherapy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; C507749:cancer-testis antigen P1A, mouse; D000077209:Decitabine; D001374:Azacitidine
keywords: 5-Aza-2′-deoxycitidine; Cancer; Photodynamic therapy; Specific antitumour immunity; Tumour associated antigens