title: Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control.
abstract: Carcinoma-associated fibroblasts (CAFs) are found in many types of cancer and play an important role in tumor growth and metastasis. Fibroblast-activation protein (FAP), which is overexpressed on the surface of CAFs, has been proposed as a universal tumor targeting antigen. However, recent studies show that FAP is also expressed on multipotent bone marrow stem cells. A systematic anti-FAP therapy may lead to severe side effects and even death. Hence, there is an urgent need of a therapy that can selectively kill CAFs without causing systemic toxicity. Herein we report a nanoparticle-based photoimmunotherapy (nano-PIT) approach that addresses the need. Specifically, we exploit ferritin, a compact nanoparticle protein cage, as a photosensitizer carrier, and we conjugate to the surface of ferritin a FAP-specific single chain variable fragment (scFv). With photoirradiation, the enabled nano-PIT efficiently eliminates CAFs in tumors but causes little damage to healthy tissues due to the localized nature of the treatment. Interestingly, while not directly killing cancer cells, the nano-PIT caused efficient tumor suppression in tumor-bearing immunocompetent mice. Further investigations found that the nano-PIT led to suppressed C-X-C motif chemokine ligand 12 (CXCL12) secretion and extracellular matrix (ECM) deposition, both of which are regulated by CAFs in untreated tumors and mediate T cell exclusion that prevents physical contact between T cells and cancer cells. By selective killing of CAFs, the nano-PIT reversed the effect, leading to significantly enhanced T cell infiltration, followed by efficient tumor suppression. Our study suggests a new and safe CAF-targeted therapy and a novel strategy to modulate tumor microenvironment (TME) for enhanced immunity against cancer.
authors.affiliation: Department of Radiology, China-Japan Union Hospital, Jilin University , Changchun 130033, China.|Department of Chemistry, Bio-Imaging Research Center, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Zhen
authors.affiliation: Department of Chemistry, Bio-Imaging Research Center, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Mengzhe
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Bio-Imaging Research Center, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Hui
authors.identifier: 0000-0002-2346-8621
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Zhanhong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Medical College of Georgia, Augusta University , Augusta, Georgia 30912, United States.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Zibo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Radiology, China-Japan Union Hospital, Jilin University , Changchun 130033, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Bio-Imaging Research Center, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Jin
authors.identifier: 0000-0002-8915-6233
authors.initials: J
authors.lastname: Xie
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D056831:Coordination Complexes / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers; D010450:Endopeptidases; D018093:Gelatinases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D007211:Indoles / Q000737:chemistry; D008027:Light; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D057145:Nanoshells / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010316:Particle Size; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry; D010789:Phototherapy; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000276:immunology / Q000378:metabolism; D013499:Surface Properties; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015032:Zinc / Q000737:chemistry*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D001052:Apoferritins; D056831:Coordination Complexes; D004337:Drug Carriers; D010450:Endopeptidases; D018093:Gelatinases; D007211:Indoles; D008565:Membrane Proteins; D017319:Photosensitizing Agents; D012697:Serine Endopeptidases; D057127:Single-Chain Antibodies; D015032:Zinc; D000099167:Fibroblast Activation Protein Alpha
keywords: Photodynamic therapy; carcinoma-associated fibroblast; cytotoxic T cells; fibroblast-activation protein; immunotherapy