Tumor suppressive efficacy through augmentation of tumor-infiltrating immune cells by intratumoral injection of chemokine-expressing adenoviral vector.
Our goal in the present study was to evaluate antitumor effects and frequency of tumor-infiltrating immune cells upon intratumoral injection of RGD fiber-mutant adenoviral vector (AdRGD) encoding the chemokines CCL17, CCL19, CCL20, CCL21, CCL22, CCL27, XCL1, and CX3CL1. Among eight kinds of chemokine-expressing AdRGDs, AdRGD-CCL19 injection most efficiently induced infiltration of T cells into established B16BL6 tumor parenchyma, whereas most of these T cells were perforin-negative in immunohistochemical analysis. Additionally, the growth of AdRGD-CCL19-injected tumors decreased only slightly as well as that of other tumors treated with each chemokine-expressing AdRGD, which indicated that accumulation of naive T cells in tumor tissue does not effectively damage the tumor cells. Tumor-bearing mice, in which B16BL6-specific T cells were elicited by dendritic cell-based immunization, demonstrated that intratumoral injection of AdRGD-CCL17, -CCL22, or -CCL27 could considerably suppress tumor growth and attract activated T cells. On the other hand, AdRGD-CCL19-injection in the immunized mice showed slight increase of tumor-infiltrating T cells compared to treatment using control vector. Collectively, although AdRGD-mediated chemokine gene transduction into established tumors would be very useful for augmentation of tumor-infiltrating immune cells, a combinational treatment that can systemically induce tumor-specific effector T cells is necessary for satisfactory antitumor efficacy.
Okada
N
N
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, Japan. okada@mb.kyoto-phu.ac.jp
Sasaki
A
A
Niwa
M
M
Okada
Y
Y
Hatanaka
Y
Y
Tani
Y
Y
Mizuguchi
H
H
Nakagawa
S
S
Fujita
T
T
Yamamoto
A
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009842:Oligopeptides / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic; D058951:gp100 Melanoma Antigen
D036022:Capsid Proteins; D018925:Chemokines; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen; C047981:arginyl-glycyl-aspartic acid