A Combination Therapy of Bortezomib, CXCR4 Inhibitor and Checkpoint Inhibitor is Effective in Cholangiocarcinoma in vivo

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) as well as matched CAFs. While ePDOs were sensitive to bortezomib, we found that matched cPDOs were resistant, most likely secondary to stroma. Mechanistically, this resistance was correlated with over-expression of CXCR4 in the CAFs of cPDO. In accord with a role of CXCR4 in 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 via increased cytotoxic T lymphocyte infiltration and decreased macrophages in the TME. This novel cancer/stroma/immune triple treatment holds great promise for the treatment of CCA. Further studies are needed to evaluate the translational potential of this approach.

Funding Information: This study was supported by Maryland Innovation Initiative (MII) Grants #0118-008_2 and #0320- 008 to Florin M. Selaru and Hai-Quan Mao.

Declaration of Interests: The authors have declared that no conflict of interest exists.

Ethics Approval Statement: Fresh human CCA specimens were collected at surgery at The Johns Hopkins Hospital under and informed consent approved by the Institutional Review Board. Approval from the Animal Care and Use Committee (ACUC) at the Johns Hopkins University was obtained.

Keywords: Cholangiocarcinoma, Organoids, CXCR4 inhibitor, Bortezomib, tumor infiltration Tlymphocyte, anti-PD1, immune therapy