Sorafenib inhibits interferon production by plasmacytoid dendritic cells in hepatocellular carcinoma

Abstract

Background Sorafenib is a multi-kinase inhibitor that shows antitumor activity in advanced hepatocellular carcinoma. Sorafenib exerts a regulatory effect on immune cells, including T cells, natural killer cells and dendritic cells. Studies have shown that plasmacytoid dendritic cells (pDCs) are functionally impaired in cancer tissues or produce low type I interferon alpha (IFNα) in cancer microenvironments. However, the effects of sorafenib on the function of pDCs have not been evaluated in detail. Methods Normal and patient PBMCs were stimulated with CpG-A to evaluate IFNα production with Flow cytometry and ELISA. Result We analyzed the production of IFNα by PBMCs in patients with advanced HCC under sorafenib treatment. We found that sorafenib-treated HCC patients produced less IFNα than untreated patients. Furthermore, we demonstrated that sorafenib suppressed the production of IFNα by PBMCs or pDCs from heathy donors in a concentration-dependent manner. Conclusion Sorafenib suppressed pDCs function. Given that sorafenib is a currently recommended targeted therapeutic agent against cancer, our results suggest that its immunosuppressive effect on pDCs should be considered during treatment.

Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer

“…A contrasting immunosuppressive effect of sorafenib was also observed in various studies. Sorafenib was shown to inhibit T-cell proliferation [ 45 ], which might be caused by suppressive dendritic cells or reduced plasmacytoid dendritic cells [ 42 , 46 , 47 ]. On the other hand, lenvatinib has been shown to mount an anti-tumor immunity response.…”

The Multifaceted Functionality of Plasmacytoid Dendritic Cells in Gastrointestinal Cancers: A Potential Therapeutic Target?

“…This severely impairs anti-tumor immunity. Regarding the impact on pDCs, sorafenib-treated HCC patients produced less IFN-α then untreated patients [ 108 ]. Furthermore, ex vivo analyses showed that in pDCs of HCC patients, the application of sorafenib significantly reduced IFN-α production [ 108 ].…”

“…Regarding the impact on pDCs, sorafenib-treated HCC patients produced less IFN-α then untreated patients [ 108 ]. Furthermore, ex vivo analyses showed that in pDCs of HCC patients, the application of sorafenib significantly reduced IFN-α production [ 108 ]. However, sorafenib primarily exerts its potent effect directly on tumor cells, resulting in a relatively modest influence on the immunogenic or tolerogenic status of pDCs.…”