Enhancing key radiation induced phenotypic changes by inhibition of the 26S proteasome in order to better stimulate immune responses (935.2)

Abstract

Radiotherapy has been extensively used for cancer therapies and sub‐lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T‐cell‐mediated immune attack. Inhibition of the ubiquitin‐proteasome system causes inhibition of cell proliferation in all cells, including cancer cells, which is a promising strategy of cancer therapy. The objective of this study is to investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in colorectal and breast cancer cells. Here, two colorectal carcinoma cell lines (HCT116 and SW620) and two breast cancer cell lines (MDA231 and MCF7) were examined for changes in expression of multiple co‐stimulatory molecules and death receptors. Our results indicate a combination of 26S proteasome inhibition and sub‐lethal radiation significantly increases the sensitivity of carcinoma cells to apoptosis. Combination treatment upregulates cell surface expression of multiple death receptors (DR4, DR5 and CD95) and co‐stimulatory molecules (OX40L and 41BBL) by increasing transcriptional activation of each gene. Our studies show for the first time that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor‐specific T‐cell survival and activation.