Sub-lethal doses of radiation can modulate gene expression, making
tumor cells more susceptible to T-cell-mediated immune attack.
Proteasome inhibitors demonstrate broad anti-
tumor activity in clinical and pre-clinical
cancer models. Here, we use a combination treatment of
proteasome inhibition and irradiation to further induce
immunomodulation of
tumor cells that could enhance
tumor-specific immune responses. We investigate the effects of the
26S proteasome inhibitor,
bortezomib, alone or in combination with
radiotherapy, on the expression of immunogenic genes in normal colon and
colorectal cancer cell lines. We examined cells for changes in the expression of several
death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of
death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of
carcinoma cells to apoptosis through FAS and
TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances
tumor cell killing by
tumor specific CD8⁺ T cells. This study suggests that combining
radiotherapy and
proteasome inhibition may simultaneously enhance
tumor immunogenicity and the induction of antitumor immunity by enhancing
tumor-specific T-cell activity.