Abstract
Abstract Although the tyrosine kinase inhibitor sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC), treatment response is often transient. Using orthotopic HCC models, we showed that resistance to sorafenib is linked to hypoxia and an associated increase in SDF1alpha and CXCR4 expression levels in tumors, which resulted in tumor desmoplasia and an increase in the infiltration of Gr1+ myeloid-derived suppressive cells, regulatory T cells and M2-type macrophages. Treatment with the CXCR4 inhibitor AMD3100 in combination with sorafenib prevented these effects. Addition of the immune checkpoint blocking antibody anti-PD1 further synergized with sorafenib and AMD3100 in delaying tumor growth and reducing metastasis. Anti-PD1 treatment significantly increased intratumoral infiltration of cytotoxic CD8+ T cells and their activity. Modulation and activation of immune responses by combining AMD3100 and anti-PD1 may be a novel approach to prevent tumor evasion from sorafenib treatment in HCC. Citation Format: Yunching Chen, Thomas Reiberger, Rakesh Ramjiawan, Mei Rosa Ng, Tai Hato, Elizabeth C. Unan, Tejaswini P. Reddy, Hiroki Ochiai, Peigen Huang, Andrew X. Zhu, Rakesh K. Jain, Dan G. Duda. CXCR4 inhibition facilitates anti-PD-1 immunotherapy by reprogramming the tumor microenvironment during sorafenib treatment in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B79.
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