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

doi:10.1016/j.isci.2023.106095

A combination therapy of bortezomib, CXCR4 inhibitor, and checkpoint inhibitor is effective in cholangiocarcinoma in vivo

iScience. 2023 Jan 31;26(3):106095. doi: 10.1016/j.isci.2023.106095. eCollection 2023 Mar 17.

Authors

Ling Li¹, Yang Zhou^{2

3}, Yicheng Zhang^{2

3}, Haijie Hu¹, Hai-Quan Mao^{2

3

4

5}, Florin M Selaru^{1

2

6}

Affiliations

¹ Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
² Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21205, USA.
³ Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

Abstract

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.

Keywords: cancer; drugs; microenvironment.