A Multifunctional Chimeric Chaperone Serves as a Novel Immune Modulator Inducing Therapeutic Antitumor Immunity

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 7; pp. 2093 - 2103
• Main Authors: XIAOFEI YU, CHUNQING GUO, HUANFA YI, JIE QIAN, FISHER, Paul B, SUBJECK, John R, WANG, Xiang-Yang
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2013
• Subjects: Adenoviridae - genetics; Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Cancer Vaccines - therapeutic use; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Dendritic Cells - immunology; Dendritic Cells - metabolism; Flagellin - genetics; Flagellin - immunology; Flagellin - metabolism; Glycoproteins - genetics; Glycoproteins - immunology; Glycoproteins - metabolism; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - immunology; HSP70 Heat-Shock Proteins - metabolism; Humans; Immunoenzyme Techniques; Immunotherapy; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Male; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Molecular Chaperones - genetics; Molecular Chaperones - immunology; Molecular Chaperones - metabolism; NF-kappa B; Pharmacology. Drug treatments; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tumor Cells, Cultured; Tumors; Antineoplastic agent; Immunomodulator; Treatment; Chimerism; Immunity; Chaperone
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-1740

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.