Resistance to tyrosine kinase inhibitor (TKI) confers an immunosuppressive microenvironment and cross-resistance to immunotherapy through intratumoral AXL/PDPK1 signaling axis in liver cancer

Abstract

Systemic therapy is the current standard of care for unresectable advanced hepatocellular carcinoma (HCC), the most malignant form of liver cancer. Clinical practice guideline for HCC includes the management of the second-line immunotherapies after patients become unresponsive to first-line targeted therapies using tyrosine kinase inhibitors (TKI), which is expected to generate optimal therapeutic effect due to the distinct mechanism of action between TKIs and immunotherapies. However, evidence from clinical trials suggests that the response to immunotherapy following TKI treatment is often compromised in TKI-resistant HCC as compared with treatment-naïve HCC, indicating a potential cross-resistance to immunotherapy, which impedes the optimal therapeutic effect of the second-line immunotherapies. In the present study, we first explored the therapeutic effect of anti-PD-1 immunotherapy in TKI-resistant HCC and successfully validated the putative cross-resistance to immunotherapy after TKI treatment. We further observed that TKI-resistant HCC exhibits an immune-evasive microenvironment, characterized by decreased CD8+ T cell and dendritic cell infiltration. This is potentially caused by the intratumoral activation of receptor tyrosine kinase AXL and its downstream target PDPK1 which protect TKI-resistant HCC cells from mitochondrial oxidative stress and the cytosolic leakage of mitochondrial DNA, which subsequently suppresses cGAS-STING together with its downstream interferon pathways and immunogenic cell death. Genetic manipulation of AXL and PDPK1 in TKI-resistant HCC cells abrogated the protective effect and thus activated the immunogenic responses. Blockade of AXL with a selective inhibitor BGB324 re-sensitized TKI-resistant HCC to anti-PD-1 treatment. The current findings suggest that targeting AXL/PDPK1 signaling axis might overcome cross-resistance to second-line immunotherapy for HCC patients who progress on TKI treatment.