title: Photosensitizer and Light Pave the Way for Cytosolic Targeting and Generation of Cytosolic CD8 T Cells Using PLGA Vaccine Particles.
abstract: The generation of CTLs is crucial in the immunological fight against cancer and many infectious diseases. To achieve this, vaccine Ags need to be targeted to the cytosol of dendritic cells, which can activate CD8 T cells via MHC class I (MHCI). Therefore, such targeting has become one of the major objectives of vaccine research. In this study, we aimed to bypass the unwanted and default MHC class II Ag presentation and trigger MHCI presentation by using a photosensitizer that, upon light activation, would facilitate cytosolic targeting of codelivered Ag. Poly(lactide-co-glycolide) microparticles ∼1 μm size were loaded with OVA and the photosensitizer tetraphenyl chlorine disulphonate (TPCS2a) and administered intradermally in mice, which were illuminated 1 d later for activation of the photosensitizer. Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-γ, TNF-α, and IL-2, and prevention of tumor growth. Cytotoxicity was demonstrated by granzyme B production in vitro and by in vivo killing of CFSE-labeled targets. CD4-dependent Ab responses were abrogated in mice immunized with TPCS2a-containing particles, suggesting that photosensitization facilitated a shift from default MHC class II toward MHCI Ag presentation. Hence, vaccine particles with Ag and photosensitizers proved an effective vehicle or adjuvant for stimulation of CTLs, and they may find potential application in therapeutic cancer vaccination and in prophylactic and therapeutic vaccination against intracellular infections.
authors.affiliation: Institute of Pharmaceutical Sciences, Federal Institute of Technology Zurich, 8093 Zurich, Switzerland; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, Italy; Vaccine Chemistry and Formulation Unit, Novartis Vaccines, 53100 Siena, Italy;
authors.forename: Cristina
authors.initials: C
authors.lastname: Bruno
authors.affiliation: Department of Dermatology, University of Zurich, 8091 Zurich, Switzerland; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Waeckerle-Men
authors.affiliation: Department of Dermatology, University of Zurich, 8091 Zurich, Switzerland; and Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway.
authors.forename: Monika
authors.initials: M
authors.lastname: Håkerud
authors.affiliation: Department of Dermatology, University of Zurich, 8091 Zurich, Switzerland; and.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kündig
authors.affiliation: Institute of Pharmaceutical Sciences, Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
authors.forename: Bruno
authors.initials: B
authors.lastname: Gander
authors.affiliation: Department of Dermatology, University of Zurich, 8091 Zurich, Switzerland; and pal.johansen@usz.ch.
authors.forename: Pål
authors.initials: P
authors.lastname: Johansen
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003600:Cytosol / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D007114:Immunization; D007271:Injections, Intradermal; D007376:Interleukin-2 / Q000096:biosynthesis; D019344:Lactic Acid / Q000737:chemistry; D008027:Light; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011166:Porphyrins / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004337:Drug Carriers; D007376:Interleukin-2; D017319:Photosensitizing Agents; D011166:Porphyrins; D014409:Tumor Necrosis Factor-alpha; C559366:meso-tetraphenyl chlorin disulphonate; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin; D053804:Granzymes