title: Enhancement of tumor-specific T cell-mediated immunity in dendritic cell-based vaccines by Mycobacterium tuberculosis heat shock protein X.
abstract: Despite the potential for stimulation of robust antitumor immunity by dendritic cells (DCs), clinical applications of DC-based immunotherapy are limited by the low potency in generating tumor Ag-specific T cell responses. Therefore, optimal conditions for generating potent immunostimulatory DCs that overcome tolerance and suppression are key factors in DC-based tumor immunotherapy. In this study, we demonstrate that use of the Mycobacterium tuberculosis heat shock protein X (HspX) as an immunoadjuvant in DC-based tumor immunotherapy has significant potential in therapeutics. In particular, the treatment aids the induction of tumor-reactive T cell responses, especially tumor-specific CTLs. The HspX protein induces DC maturation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IFN-β) through TLR4 binding partially mediated by both the MyD88 and the TRIF signaling pathways. We employed two models of tumor progression and metastasis to evaluate HspX-stimulated DCs in vivo. The administration of HspX-stimulated DCs increased the activation of naive T cells, effectively polarizing the CD4(+) and CD8(+) T cells to secrete IFN-γ, as well as enhanced the cytotoxicity of splenocytes against HPV-16 E7 (E7)-expressing TC-1 murine tumor cells in therapeutic experimental animals. Moreover, the metastatic capacity of B16-BL6 melanoma cancer cells toward the lungs was remarkably attenuated in mice that received HspX-stimulated DCs. In conclusion, the high therapeutic response rates with tumor-targeted Th1-type T cell immunity as a result of HspX-stimulated DCs in two models suggest that HspX harnesses the exquisite immunological power and specificity of DCs for the treatment of tumors.
authors.affiliation: Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea;
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, South Korea;
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Physiology, College of Medicine, Korea University, Seoul 136-705, South Korea;
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea;
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea;
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.affiliation: Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea;
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, South Korea;
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, South Korea;
authors.forename: Hong Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea;
authors.forename: Won Sun
authors.initials: WS
authors.lastname: Park
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, South Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea;
authors.forename: Han Wool
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, South Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea;
authors.forename: Cheol-Heui
authors.initials: CH
authors.lastname: Yun
authors.affiliation: Yongsan Hospital College of Medicine, Chung-Ang University, Seoul 156-756, South Korea;
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD 21205; and Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea; immun3023@kku.ac.kr.
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage* / Q000276:immunology*; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000276:immunology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C118127:HspX protein, Mycobacterium tuberculosis