Big tumor regression induced by GM-CSF gene-modified 3LL tumor cells via facilitating DC maturation and deviation toward CD11c+CD8alpha+ subset.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a powerful immune-stimulating factor that helps to generate a systemic, strong, and long-lasting immune response. However, whether the transduction of GM-CSF to tumor cell results in tumor regression and optimizes local immune microenvironment remains to be investigated. In this study, using an experimental murine tumor model, we demonstrated that the in vivo growth of 3LL tumor cells modified with the GM-CSF gene (3LL-GM) was inhibited even when the tumor diameter was over 7 mm (big tumor), and mice inoculated with GM-CSF gene-modified 3LL cells survived over 90 days, whereas mice inoculated with control parental 3LL cells and 3LL cells transduced with control vector all succumbed to the tumor by day 17 after tumor inoculation. Further analysis showed that targeted expression of GM-CSF in 3LL tumor cells markedly enhanced the systemic antitumor effect, including specific lymphocytes proliferation, cytotoxicity against 3LL tumor, and increased production of IFN-gamma. GM-CSF gene-modified 3LL cells significantly protected the mice from the parental 3LL tumor challenge. More importantly, the percentage of dendritic cells (DCs) in tumor site was greatly increased and the DCs differentiated into CD11c(+)CD8alpha(+) cells, which were reported to be able to benefit the induction of CD8(+) cytotoxic T lymphocytes (CTLs) that contribute to tumor regression. Our research indicated that GM-CSF could optimize the immune microenvironment in the tumor site, which provides a potent approach for immunotherapy of tumors.
Lin
Yi
Y
Department of Immunology, Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai, P. R. China.
Xiong
Sidong
S
Zhang
Lei
L
Zhang
Yi
Y
Cai
Yuchan
Y
Xu
Lin
L
Chu
Yiwei
Y
D000818:Animals; D001483:Base Sequence; D039521:CD11c Antigen / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins
D039521:CD11c Antigen; D016827:CD8 Antigens; C431698:CD8alpha antigen; D017931:DNA Primers; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor