Abstract
BackgroundhTERTC27 is a 27 kDa C-terminal polypeptide of human telomerase reverse transcriptase that has previously been shown to reduce tumorigenicity of HeLa cells and suppress growth of xenografted glioblastoma in nude mice. Although ectopic expression of hTERTC27 upregulated genes that are involved in apoptosis, cell cycle, and immune response, the mechanism for hTERTC27-induced tumor suppression has not been completely elucidated. Since hTERT was identified as a universal tumor-associated antigen, we hypothesize that hTERTC27 inhibits tumor growth in vivo through activation of anti-tumor immune response.Methodology/Principal FindingImmunocopetent C57BL/6 mice were used for mouse B16 melanoma model. Mice bearing B16 melanoma were administered rAAV-/rAdv viral cocktail expressing hTERTC27, and tumor growth was monitored after viral cocktail treatment. Blood and splenocytes were used to determine the level of cytokines and the activity of immune cells, respectively. B16 tumor growth was significantly inhibited by subcutaneous administration of a single dose of 1.5×1011 vg rAAV-hTERTC27 and 2.5×109 pfu rAdv-hTERTC27 viral cocktail (rAAV-/rAdv-hTERTC27). The population and cytotoxicity of NK cells in the mice were significantly augmented by rAAV-/rAdv-hTERTC27 treatment, and selective depletion of the NK cell population in mice by intraperitoneal injection of anti-GM1 antibody abrogated the growth suppression of melanoma induced by rAAV-/rAdv-hTERTC27 administration.ConclusionActivation of NK cells by administration of rAAV-/rAdv-hTERTC27 is critical for growth suppression of melanoma in mouse model.
Highlights
The frequency of melanoma cases in Western countries has risen rapidly over the last years, and melanoma has become one of the most fatal cancers [1]
Activation of NK cells by administration of recombinant adeno-associated virus (rAAV)-/recombinant adenovirus (rAdv)-hTERTC27 is critical for growth suppression of melanoma in mouse model
Results rAAV-/rAdv-hTERTC27 viral cocktail is more effective than either virus alone in suppressing the growth of B16 melanoma in C57BL/6 mice
Summary
The frequency of melanoma cases in Western countries has risen rapidly over the last years, and melanoma has become one of the most fatal cancers [1]. The non-specificity and significant side effects of these therapies greatly limit their effective use in patients [2,7,8,9]. Biochemotherapy, a combination therapy of cytokine adjuvant with chemotherapeutic agents, has been shown to improve response rates but not overall survival. Several Phase II/III clinical trials are ongoing for the use of CTLA4 monoclonal antibodies as a new promising strategy for the treatment of metastatic melanoma [12]; significant autoimmunerelated side effects have been increasingly observed [13,14,15]. On the other hand, exhibit higher specificity and less toxicity, and their development has made rapid progress in recent decades [10,16,17], but the therapeutic efficacy has been very low with the reported overall objective response rate of only 3.3% [18]. Since hTERT was identified as a universal tumor-associated antigen, we hypothesize that hTERTC27 inhibits tumor growth in vivo through activation of anti-tumor immune response
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