Abstract

Abstract Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Anti-angiogenic therapy with bevacizumab has been proven efficacious in metastatic CRC. However, the improvement in overall survival has been modest and rather disappointing. Thus, there is an urgent need to identify the underlying mechanisms responsible for the resistance to anti-angiogenic therapy and develop strategies to overcome it. Clinical and preclinical interest in tumor immunotherapy has been renewed in a significant manner recently. However, the role of the immune microenvironment in colorectal cancer resistance to anti-angiogenic therapy is not well understood. We have developed miniaturized confocal endomicroscopy technique for spontaneous CRC models in mice. We also established a novel cecum window recently. These unique systems enable us to monitor the CRC and its immune microenvironment longitudinally with a video-rate intravital multi-photon microscope. Using these CRC models and in vivo imaging methods, we found that anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody increases infiltration of Gr1+ myeloid-derived suppressor cells (MDSCs) and they alter the tumor microenvironment toward an immune-suppressive condition to avoid attack of the host immune system. We also found that the Gr1+ MDSCs express CXCR4, which has important roles in cell-autonomous survival and chemotaxis, through its downstream signaling pathways. When we treat the VEGF signaling blocker together with a CXCR4-specific inhibitor, the level of the Gr1+ MDSC infiltration is dramatically decreased nearly to that of control group, and subsequently, tumor growth is significantly delayed compared to separate treatment of each inhibitor. Taken together, we identified Gr1+ MDSCs as key players in tumor resistance to anti-angiogenic therapy in CRCs, and the blockade of CXCR4 signaling has a synergistic effect with anti-VEGF therapy, proven by state-of-the-art in vivo imaging modalities. Citation Format: Keehoon Jung, Takahiro Heishi, Andy Yun, Timothy P. Padera, Rakesh K. Jain, Dai Fukumura. Targeting the immune microenvironment to improve colorectal cancer anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4195.

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