title: Depletion of tumor-associated macrophages enhances the anti-tumor immunity induced by a Toll-like receptor agonist-conjugated peptide.
abstract: It has been reported that lipopeptides can be used to elicit cytotoxic T lymphocyte (CTL) responses against viral diseases and cancer. In our previous study, we determined that mono-palmitoylated peptides can enhance anti-tumor responses in the absence of adjuvant activity. To investigate whether di-palmitoylated peptides with TLR2 agonist activity are able to induce anti-tumor immunity, we synthesized a di-palmitic acid-conjugated long peptide that contains a murine CTL epitope of HPV E749-57 (Pam2IDG). Pam2IDG stimulated the maturation of bone marrow-derived dendritic cells (BMDCs) through TLR2/6. After immunization, Pam2IDG induced higher levels of T cell responses than those obtained with its non-lipidated counterpart (IDG). In the prophylactic model, Pam2IDG immunization completely inhibited tumor growth, whereas IDG immunization was unable to inhibit tumor growth. However, Pam2IDG immunization could not effectively inhibit the growth of established tumors. Therefore, we further investigated whether the depletion of immunosuppressive factors could improve the therapeutic effects of Pam2IDG. Our data indicate that treatment with Pam2IDG combined with clodronate/liposome delays tumor growth and increases the survival rate. We also observed that the therapeutic effects of Pam2IDG are improved by diminishing the function of tumor-associate macrophages (TAMs) and through the use of an IL10 receptor blocking antibody or a Cyclooxygenase 2 (Cox-2) inhibitor. In conclusion, the depletion of TAMs may enhance the anti-tumor immunity of a TLR2 agonist-conjugated peptide.
authors.affiliation: a Graduate Institute of Life Sciences; National Defense Medical Center ; Taipei , Taiwan.
authors.forename: Kuan-Yin
authors.initials: KY
authors.lastname: Shen
authors.forename: Ying-Chyi
authors.initials: YC
authors.lastname: Song
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Chen
authors.forename: Pele
authors.initials: P
authors.lastname: Chong
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000627:therapeutic use; D004002:Clodronic Acid / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology; D007114:Immunization; D007167:Immunotherapy; D055666:Lipopeptides / Q000276:immunology / Q000627:therapeutic use*; D054878:Lipoylation; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D019308:Palmitic Acid / Q000737:chemistry / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000737:chemistry / Q000276:immunology; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors / Q000276:immunology; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D052246:Cyclooxygenase 2 Inhibitors; D055666:Lipopeptides; D050725:Papillomavirus E7 Proteins; D053701:Receptors, Interleukin-10; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D004002:Clodronic Acid; D019308:Palmitic Acid
keywords: IL10; Toll-like receptor; cyclooxygenase; immunotherapy; macrophage; peptide