title: A Toll-like receptor 2 agonist-fused antigen enhanced antitumor immunity by increasing antigen presentation and the CD8 memory T cells population.
abstract: The induction of long-lived effector CD8+ T cells is key to the development of efficient cancer vaccines. In this study, we demonstrated that a Toll-like receptor 2 (TLR2) agonist-fused antigen increased antigen presentation via TLR2 signaling and induced effector memory-like CD8+ T cells against cancer after immunization. The N-terminus of ovalbumin (OVA) was biologically fused with a bacterial lipid moiety TLR2 agonist to produce a recombinant lipidated ovalbumin (rlipo-OVA). We demonstrated that rlipo-OVA activated bone marrow-derived dendritic cells (BM-DCs) maturation and increased antigen presentation by major histocompatibility complex (MHC) class I via TLR2. After immunization, rlipo-OVA skewed the immune response towards T helper (Th) 1 and induced OVA-specific cytotoxic T lymphocyte (CTL) responses. Moreover, immunization with rlipo-OVA induced higher numbers of effector memory (CD44+CD62L-) CD8+ T cells compared with recombinant ovalbumin (rOVA) alone or rOVA mixed with the TLR2 agonist Pam3CSK4. Accordingly, the CD27+CD43+ effector memory CD8+ T cells expressed high levels of the long-lived CD127 marker. The administration of rlipo-OVA could inhibit tumor growth, but the anti-tumor effects were lost after the depletion of CD8 or CD127 cells in vivo. These findings suggested that the TLR2 agonist-fused antigen induced long-lived memory CD8+ T cells for efficient cancer therapy.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.|National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan.
authors.forename: Chiao-Chieh
authors.initials: CC
authors.lastname: Wu
authors.affiliation: National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan.|Graduate Institute of Immunology, China Medical University, Taichung 40402, Taiwan.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Liu
authors.affiliation: National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan.|Graduate Institute of Immunology, China Medical University, Taichung 40402, Taiwan.
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Chen
authors.affiliation: National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan.
authors.forename: Kuan-Yin
authors.initials: KY
authors.lastname: Shen
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.|National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan.|Graduate Institute of Immunology, China Medical University, Taichung 40402, Taiwan.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Leng
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D007942:Leukemia, Experimental / Q000276:immunology / Q000628:therapy*; D055666:Lipopeptides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D053699:Interleukin-7 Receptor alpha Subunit; D055666:Lipopeptides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C508075:Pam(3)CSK(4) peptide; D011993:Recombinant Fusion Proteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D010047:Ovalbumin
keywords: Toll-like receptor 2; antigen presentation; memory T cells; rlipo-immunogen; tumor regression