title: A multifunctional chimeric chaperone serves as a novel immune modulator inducing therapeutic antitumor immunity.
abstract: Converting the immunosuppressive tumor environment into one that is favorable to the induction of antitumor immunity is indispensable for effective cancer immunotherapy. Here, we strategically incorporate a pathogen (i.e., flagellin)-derived, NF-κB-stimulating "danger" signal into the large stress protein or chaperone Grp170 (HYOU1/ORP150) that was previously shown to facilitate antigen crosspresentation. This engineered chimeric molecule (i.e., Flagrp170) is capable of transporting tumor antigens and concurrently inducing functional activation of dendritic cells (DC). Intratumoral administration of adenoviruses expressing Flagrp170 induces a superior antitumor response against B16 melanoma and its distant lung metastasis compared with unmodified Grp170 and flagellin. The enhanced tumor destruction is accompanied with significantly increased tumor infiltration by CD8(+) cells as well as elevation of IFN-γ and interleukin (IL)-12 levels in the tumor sites. In situ Ad.Flagrp170 therapy provokes systemic activation of CTLs that recognize several antigens naturally expressing in melanoma (e.g., gp100/PMEL and TRP2/DCT). The mechanistic studies using CD11c-DTR transgenic mice and Batf3-deficient mice reveal that CD8α(+) DCs are required for the improved T-cell crosspriming. Antibody neutralization assays show that IL-12 and IFN-γ are essential for the Flagrp170-elicited antitumor response, which also involves CD8(+) T cells and natural killer cells. The therapeutic efficacy of Flagrp170 and its immunostimulating activity are also confirmed in mouse prostate cancer and colon carcinoma. Together, targeting the tumor microenvironment with this chimeric chaperone is highly effective in mobilizing or restoring antitumor immunity, supporting the potential therapeutic use of this novel immunomodulator in the treatment of metastatic diseases.
authors: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors: Xiaofei
authors: X
authors: Yu
authors: Chunqing
authors: C
authors: Guo
authors: Huanfa
authors: H
authors: Yi
authors: Jie
authors: J
authors: Qian
authors: Paul B
authors: PB
authors: Fisher
authors: John R
authors: JR
authors: Subjeck
authors: Xiang-Yang
authors: XY
authors: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005408:Flagellin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D019496:Cancer Vaccines; D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D012333:RNA, Messenger; C098410:glucose-regulated protein 170; D005408:Flagellin