Abstract
Tumor cells tend to behave differently in response to immune selective conditions. Contrary to those in therapeutic antitumor conditions, tumor cells in prophylactic antitumor conditions lose antigen expression for antitumor immune escape. Here, using a CT26/HER2 tumor model, we investigate the underlying mechanism(s). We selected tumor cell variants (CT26/HER2-A1 and -A2) displaying resistance to antitumor protective immunity and loss of HER2 antigen expression. These immune-resistant cells failed to induce Ag-specific IgG and IFN-γ responses while forming tumors at the same rate as CT26/HER2 cells. RT-PCR, qRT-PCR, PCR, Western blot and DNA sequencing analyses demonstrated that HER2 expression was inhibited at the post-transcriptional level in these immune-resistant cells, suggesting that tumor cells may escape antitumor immunity through the post-transcriptional regulation of antigen gene expression. The proteasome and lysosomal protein degradation pathways were not responsible for antigen loss, as determined by an inhibitor assay. Finally, HER2 mRNA was found to be not present in the monosomes and polysomes of CT26/HER2-A2 cells, as opposed to CT26/HER2 cells, suggesting that the translation activity of HER2 mRNAs may be suppressed in these immune-resistant cells. Taken together, our results report a new mechanism by which tumor cells respond to antitumor protective immunity for antitumor immune evasion.
Highlights
Human epidermal growth factor receptor 2 [HER2], as an oncogenic protein, has an important function in the development of breast cancer[1,2]
We observed in a prophylactic CT26/HER2 tumor model that despite their CTL induction status, a few mice formed tumors when they were challenged with a high number of tumor cells
Immune cells isolated from HER2 vaccine-immunized mice produced significantly more IFN-γ than those from naïve mice, indicating that this increased amount of IFN-γ might be produced from Ag-specific T cells that were induced by HER2 DNA vaccines
Summary
Human epidermal growth factor receptor 2 [HER2] ( known as Her-2/neu and erbB-2), as an oncogenic protein, has an important function in the development of breast cancer[1,2]. It has been reported that immune selection pressures allow tumor cells to develop stem-like phenotypes with CTL resistance in the TC-1 model[20]. In this context, it is likely that antitumor immunity may serve as a biological selective pressure that promotes the emergence of immune escape tumor cell variants, as suggested by Schreiber’s group[21]. The loss of tumor antigen was found to be mediated by inhibiting the translational activity of its mRNAs, but not through the modification of protein degradation pathways This is a new finding that immune selection pressure may allow tumor cells to inhibit the translation activity of their antigen mRNAs at the post-transcriptional level and that the loss of tumor antigen is responsible for tumor immune escape
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