Targeting AXL/PDK1 signaling axis activates immunogenic cell death in liver cancer

Hepatocellular carcinoma (HCC) is the most malignant form of primary liver cancers with poor prognosis. Majority of the cases are diagnosed in advanced stages where therapeutic options are limited and the response rates are low. There is an unmet clinical need for more effective therapeutic treatment. AXL is a receptor tyrosine kinase which belongs to the family of TAM receptors. Overexpression of AXL has been reported in multiple cancers, including HCC. We and others have also reported an up-regulation of AXL in sorafenib-resistant HCC. However, its role in regulating anti-tumor immunity in HCC is not fully understood. In this study, we observed an immunosuppressive gene signature in sorafenib-resistant HCC by RNA-Seq and pathway enrichment analysis. Genetic manipulation and pharmacological inhibition of AXL promoted immunogenic cell death in sorafenib-resistant HCC cells, as evident by increased surface calreticulin and HMGB1 secretion. PDK1, a key modulatory kinase downstream of AXL in the PI3K/Akt pathway, was also up-regulated in sorafenib-resistant HCC. Knockdown of PDK1 similarly led to an increased immunogenic cell death. In a sorafenib-resistant immunocompetent mouse HCC model, blockade of AXL with a selective AXL inhibitor increased tumor-infiltrating activated and proliferating CD8+ T cells, resulting in tumor suppression and prolonged survival of the mice. Taken together, our findings suggest that targeting the AXL/PDK1 signaling axis could be a viable therapeutic option which enhances anti-tumor immunity for the treatment of HCC. Citation Format: Yunong Xie, Lei Zhou, Cheuk Yin Lin, Terence Lee, Jin Ding, Stephanie Ma, Man Tong. Targeting AXL/PDK1 signaling axis activates immunogenic cell death in liver cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P236.