Human sodium/iodide symporter-mediated radioiodine gene therapy enhances the killing activities of CTLs in a mouse tumor model.
We examined whether human sodium/iodide symporter (hNIS) radioiodine gene therapy can modulate the phenotype of cancer cells and enhance the killing activities of CTLs in a mouse tumor model. Various doses of I-131 (75, 300, 600, 1,200, and 2,400 microCi/5 mL) were incubated with hNIS-expressing colon cancer (CT26/hNIS) and parental cells (CT26), and numbers of MHC class I and Fas-expressing cells were determined by fluorescence-activated cell sorting (FACS). In addition, CT26/hNIS or CT26 tumor-bearing mice were treated with 1,200 microCi of I-131, and percentages of MHC class I and Fas-expressing tumor cells were determined by FACS. The levels of tumor-infiltrating CD8+IFNgamma+ and CD11c+CD86+ cells and CTL killing activities were measured in CT26/hNIS tumor-bearing mice (treated with PBS or 1,200 microCi of I-131) by FACS and lactate dehydrogenase assay, respectively. MHC class I and Fas gene expressions were markedly upregulated in CT26/hNIS cells, but not in CT26 cells, in an I-131 dose-dependent manner. The level of MHC class I and Fas-expressing cancer cell were 4.5-fold and 2.1-fold higher in CT26/hNIS tumors than in CT26 tumors, respectively (P < 0.01). Interestingly, numbers of tumor-infiltrating CD8+IFNgamma+ cells and CD11c+CD86+ cells were 5-fold and 2.5-fold higher in I-131-treated tumors than in PBS tumors, respectively (P < 0.001). Furthermore, CTL assays showed significantly more specific tumor cell lysis in I-131 tumors than in PBS tumors (P < 0.01). Our findings suggest that hNIS radioiodine gene therapy can generate tumor-associated immunity in tumor microenvironments and enhance the killing activities of CTLs.
Jeon
Yong Hyun
YH
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
Choi
Yun
Y
Kim
Chul Woo
CW
Kim
Young-Hwa
YH
Youn
Hyewon
H
Lee
Jaetae
J
Chung
June-Key
JK
D000818:Animals; D051940:B7-2 Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D015316:Genetic Therapy; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007457:Iodine Radioisotopes; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D010641:Phenotype; D027981:Symporters / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
D051940:B7-2 Antigen; D039521:CD11c Antigen; D007371:Interferon-gamma; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters