An Oncolytic Adenovirus Encoding Decorin and Granulocyte Macrophage Colony Stimulating Factor Inhibits Tumor Growth in a Colorectal Tumor Model by Targeting Pro-Tumorigenic Signals and via Immune Activation

摘要

In advanced and metastatic stages of colorectal cancer (CRC), reduced sensitivity to conventional strategies is still a major obstacle to successful treatments. Decorin is an important regulator in the development and progression of various cancers. To examine if CRC patients have altered decorin levels, expression of decorin and its target genes, Met and vascular endothelial growth factor A (VEGFA), were analyzed in their tumors. Compared to normal tissues, decorin expression was reduced in CRC patients' tumors, while there were increased Met and VEGFA levels. To develop a novel therapy for CRC, rAd. DCN. GM, an oncolytic adenovirus encoding decorin and granulocyte macrophage colony stimulating factor (GM-CSF), has been created. Several therapeutic strategies expressing GM-CSF have been employed in clinical trials for treating metastatic colorectal cancer. In this study, infection of CRC cells with rAd. DCN. GM expressed decorin and GM-CSF, and produced cytotoxicity. In murine CT26 xenografts, rAd. DCN. GM and control adenoviruses were administrated intratumorally on days 7 and 10, and tumor volumes were monitored over time. The study showed that rAd. DCN. GM inhibited the tumor growth and lung metastases significantly. rAd. DCN. GM induced apoptosis, inhibited proliferation, and downregulated angiogenesis and epithelial mesenchymal transition markers in the tumors. On day 12 and day 29, the immune-activation in the peripheral blood, tumors, and spleens were analyzed. rAd. DCN. GM increased CD8+ T lymphocytes in the blood, upregulated perforin and granzyme B in the tumors, inhibited transforming growth factor beta expression, and promoted dendritic-cell production in the spleen. In conclusion, rAd. DCN. GM inhibited the tumor growth and metastasis of CT26 tumors, downregulated multiple pro-tumorigenic pathways, and activated antitumor immune responses.