title: TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells.
abstract: Using TLR agonists in cancer treatment can have either beneficial or detrimental effects. Therefore, it is important to determine their effect on the tumor growth and understand the underlying mechanisms in animal tumor models. In this study, we report a general immunotherapeutic activity of a synthetic bacterial lipoprotein (BLP), a TLR1/TLR2 agonist, on established lung carcinoma, leukemia, and melanoma in mice. Systemic treatment of 3LL tumor-bearing mice with BLP, but not LPS, led to a dose-dependent tumor regression and a long-lasting protective response against tumor rechallenge. The BLP-mediated tumor remission was neither mediated by a direct tumoricidal activity nor by innate immune cells, because it lacked therapeutic effect in immunodeficient SCID mice. Instead, BLP treatment reduced the suppressive function of Foxp3(+) regulatory T cells (Tregs) and enhanced the cytotoxicity of tumor-specific CTL in vitro and in vivo. Furthermore, adoptive cotransfer of BLP-pretreated but not untreated CTL and Tregs from wild-type but not from TLR2(-/-) mice was sufficient to restore antitumor immunity in SCID mice by reciprocally modulating Treg and CTL function. These results demonstrate that the TLR1/TLR2 agonist BLP may have a general tumor therapeutic property involving reciprocal downregulation of Treg and upregulation of CTL function. This property may play an important role in the development of novel antitumor strategies.
authors.affiliation: Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Feifei
authors.initials: F
authors.lastname: Luo
authors.forename: Yuchan
authors.initials: Y
authors.lastname: Cai
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.forename: Luman
authors.initials: L
authors.lastname: Wang
authors.forename: Damo
authors.initials: D
authors.lastname: Xu
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000819:agonists / Q000138:chemical synthesis; D001426:Bacterial Proteins / Q000138:chemical synthesis / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007942:Leukemia, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008074:Lipoproteins / Q000138:chemical synthesis / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D051194:Toll-Like Receptor 1 / Q000819:agonists* / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000172:deficiency / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D008074:Lipoproteins; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2