title: Photodynamic Therapy Mediated by Nontoxic Core-Shell Nanoparticles Synergizes with Immune Checkpoint Blockade To Elicit Antitumor Immunity and Antimetastatic Effect on Breast Cancer.
abstract: An effective, nontoxic, tumor-specific immunotherapy is the ultimate goal in the battle against cancer, especially the metastatic disease. Checkpoint blockade-based immunotherapies have been shown to be extraordinarily effective but benefit only the minority of patients whose tumors have been pre-infiltrated by T cells. Here, we show that Zn-pyrophosphate (ZnP) nanoparticles loaded with the photosensitizer pyrolipid (ZnP@pyro) can kill tumor cells upon irradiation with light directly by inducing apoptosis and/or necrosis and indirectly by disrupting tumor vasculature and increasing tumor immunogenicity. Furthermore, immunogenic ZnP@pyro photodynamic therapy (PDT) treatment sensitizes tumors to checkpoint inhibition mediated by a PD-L1 antibody, not only eradicating the primary 4T1 breast tumor but also significantly preventing metastasis to the lung. The abscopal effects on both 4T1 and TUBO bilateral syngeneic mouse models further demonstrate that ZnP@pyro PDT treatment combined with anti-PD-L1 results in the eradication of light-irradiated primary tumors and the complete inhibition of untreated distant tumors by generating a systemic tumor-specific cytotoxic T cell response. These findings indicate that nanoparticle-mediated PDT can potentiate the systemic efficacy of checkpoint blockade immunotherapies by activating the innate and adaptive immune systems in tumor microenvironment.
authors.affiliation: Department of Chemistry, The University of Chicago , 929 East 57th Street, Chicago, Illinois 60637, United States.
authors.forename: Xiaopin
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Chemistry, The University of Chicago , 929 East 57th Street, Chicago, Illinois 60637, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Chan
authors.affiliation: Department of Chemistry, The University of Chicago , 929 East 57th Street, Chicago, Illinois 60637, United States.|Department of Radiation and Cellular Oncology and The Ludwig Center for Metastasis Research, The University of Chicago , 5758 South Maryland Avenue, Chicago, Illinois 60637, United States.
authors.forename: Nining
authors.initials: N
authors.lastname: Guo
authors.affiliation: Department of Chemistry, The University of Chicago , 929 East 57th Street, Chicago, Illinois 60637, United States.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Radiation and Cellular Oncology and The Ludwig Center for Metastasis Research, The University of Chicago , 5758 South Maryland Avenue, Chicago, Illinois 60637, United States.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Chemistry, The University of Chicago , 929 East 57th Street, Chicago, Illinois 60637, United States.
authors.forename: Wenbin
authors.identifier: 0000-0001-7035-7759
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000737:chemistry; D003131:Combined Modality Therapy; D011756:Diphosphates / Q000737:chemistry*; D006801:Humans; D007167:Immunotherapy; D008027:Light; D008055:Lipids / Q000737:chemistry; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009336:Necrosis; D009362:Neoplasm Metastasis; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015032:Zinc / Q000737:chemistry
chemical_list: D011756:Diphosphates; D008055:Lipids; D017319:Photosensitizing Agents; D002734:Chlorophyll; C040298:pyropheophorbide a; C107241:diphosphoric acid; D015032:Zinc