A combination therapy of bortezomib, CXCR4 inhibitor, and checkpoint inhibitor is effective in cholangiocarcinoma in vivo
Ling Li,
Yang Zhou,
Yicheng Zhang,
Haijie Hu,
Hai-Quan Mao,
Florin M. Selaru
Affiliations
Ling Li
Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Yang Zhou
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
Yicheng Zhang
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
Haijie Hu
Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Hai-Quan Mao
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Florin M. Selaru
Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Corresponding author
Summary: Cholangiocarcinoma (CCA) is a biliary tree malignancy with a dismal prognosis. Tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) has been shown to be involved in drug resistance. To model the interactions between cancer cells and the TME, we established CCA complex patient-derived organoids (cPDOs) to include epithelial PDO (ePDOs) and matched CAFs. While ePDOs were sensitive to bortezomib, we found the matched cPDOs were relatively resistant. Mechanistically, this resistance was correlated with over-expression of CXCR4 in the CAF component of cPDOs. In accord with the role of CXCR4 in the resistance to bortezomib, we found that a CXCR4 inhibitor can reverse the resistance to bortezomib in vivo. Furthermore, we found that the inhibition of CXCR4 allowed bortezomib to sensitize CCA to anti-PD1 treatment, with a significant reduction of tumor burden and long-term overall survival. This novel cancer/stroma/immune triple treatment holds great promise for the treatment of CCA.
