title: Co-operation of α-galactosylceramide-loaded tumour cells and TLR9 agonists induce potent anti-tumour responses in a murine colon cancer model.
abstract: Dendritic cells (DCs) and invariant natural killer T (iNKT) cells play important roles in linking innate immunity and adaptive immunity. Mature DCs activated by Toll-like receptor (TLR) agonists directly activate iNKT cells and the iNKT ligand α-galactosylceramide (α-Galcer) can induce DC maturation, resulting in enhanced protective immune responses. In the present study, we aimed to boost anti-tumour immunity in a murine colon cancer model by synergizing DCs and iNKT cells using α-Galcer-loaded tumour cells (tumour-Gal) and the TLR9 agonist cytosine-phosphorothioate-guanine (CpG1826). The vaccine strategy was sufficient to inhibit growth of established tumours and prolonged survival of tumour-bearing mice. Importantly, the immunization induced an adaptive memory immune response as the survivors from primary tumour inoculations were resistant to a tumour re-challenge. Furthermore, injection of tumour-Gal with CpG1826 resulted in iNKT cell activation and DC maturation as defined by interferon (IFN)-γ secretion by iNKT, natural killer (NK) cells and interleukin (IL)-12 by DCs. Immunohistochemistry analysis revealed that cluster of differentiation (CD)4(+) T-cells and CD8(+) T-cells played important roles in anti-tumour immunity. Additionally, the vaccine redirected Th2 (T-helper cell type 2) responses toward Th1 (T-helper cell type 1) responses with increases in IL-2, IFN-γ expression and decreases in IL-4 and IL-5 expression after immunization with tumour-Gal with CpG1826. Taken together, our results demonstrated a novel vaccination by synergizing tumour-Gal and CpG1826 against murine colon cancer, which can be further developed as tumour-specific immunotherapy against human cancer.
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Tiangeng
authors.initials: T
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Tuo
authors.initials: T
authors.lastname: Yi
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Mengxuan
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Xingyuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hu
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China hong.xinqiang@zs-hospital.sh.cn niu.weixin@zs-hospital.sh.cn.
authors.forename: Xinqiang
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Feng-Lin Road, Shanghai, 200032, China hong.xinqiang@zs-hospital.sh.cn niu.weixin@zs-hospital.sh.cn.
authors.forename: Weixin
authors.initials: W
authors.lastname: Niu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D005699:Galactosylceramides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C493154:alpha-galactosylceramide
keywords: Toll-like receptor 9; colon cancer; dendritic cells; invariant natural killer T (iNKT) cells; therapeutic vaccine