Abstract
In a previous study, we demonstrated that pcDNA3.1/hNIS (human sodium iodide symporter) vaccination generated hNIS-associated CD8+IFN-gamma+ (interferon-gamma) T cells, which are known to be involved in antitumor immunity. However, the immune response induced was insufficient to control tumor growth in vivo, which required a novel approach to potentiate hNIS vaccination effects. In the present study, we administered 131I radioiodine therapy prior to hNIS vaccination in CT26/hNIS tumor-bearing mice to facilitate the vaccine-induced immune response. We characterized hNIS-associated cytotoxic T-cell immune response and the antitumor effects induced by this 131I + hNIS combination therapy. The survival rates of CT26/hNIS tumor cells were significantly reduced by 131I treatment compared with the parental CT26 cells in vitro. 131I + hNIS combination therapy stably suppressed tumor growth below or near the original tumor size level of initial treatment, achieving 100% survival rates. Specifically, 131I + hNIS therapy enhanced IFN-gamma production, hNIS-associated antitumor cytotoxic T-lymphocyte (CTL) response, and induced more dendritic cells but reduced T-regulatory cells in tumor masses. Collectively, these results suggest that combined therapy effectively enhances hNIS-associated antitumor immune response, leading to CT26/hNIS tumor growth inhibition and complete survival in Balb/C mice. These findings provide a novel and effective means of treating cancer.
Highlights
M OST OF THE METHODS used to image the expression of ‘‘reporter’’ genes in rodents, primates, and humans require the use of postmortem tissue
Methods based on the use of human sodium iodide symporter as a reporter gene labeled with 124I, 125I, 131I, or 99mTc allow visualization of various biochemical processes in living tissues. hNIS is a member of the sodium/glucose cotransporter family, which transports iodide into thyroid cells.[1,2]
We showed that vaccination with hNIS-encoding plasmid enhanced hNIS-associated antitumor immunity, including the CD8+IFN-c+ T-cell response, with limited effects on in vivo tumor growth inhibition,[10] which required additional treatment to sufficiently enhance the efficacy of the hNIS vaccine
Summary
M OST OF THE METHODS used to image the expression of ‘‘reporter’’ genes in rodents, primates, and humans require the use of postmortem tissue. Methods based on the use of human sodium iodide symporter (hNIS) as a reporter gene labeled with 124I, 125I, 131I, or 99mTc allow visualization of various biochemical processes in living tissues. # 2010 BC Decker Inc normal surrounding tissues This differential expression allows effective radioisotope (131I or 188Re) therapy on the basis of its physiologic function, which influences prognosis in preclinical and clinical models.[5,6,7] Sodium iodide symporter (NIS)-specific radioiodine accumulation in cancer has been suggested to cause significant reductions in tumor mass in athymic nude mice and immunocompetent mice.[6,8,9] Cancer-specific hNIS expression is an attractive target for immunotherapy. We showed that vaccination with hNIS-encoding plasmid (pcDNA3.1/hNIS) enhanced hNIS-associated antitumor immunity, including the CD8+IFN-c+ (interferon-c) T-cell response, with limited effects on in vivo tumor growth inhibition,[10] which required additional treatment to sufficiently enhance the efficacy of the hNIS vaccine
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