Abstract
Recent clinical trials have demonstrated that immune checkpoint inhibitors are effective for only ∼20% of hepatocellular carcinoma (HCC) patients. Adjuvant hyperthermia treatment can potentially overcome barriers to immunotherapy by inducing immunogenic cell death; however, existing hyperthermia modalities are poorly optimized for immune stimulation. The purpose of this study was to evaluate the immunologic ramifications of a novel hyperthermia modality that promotes tumor-specific heat generation. An orthotopic HCC model was generated by subcapsular implantation of syngeneic McA-RH7777 hepatoma cells in female Buffalo rats (n=20). 96h following the i.v. administration of 0.5mg/kg indocyanine green (ICG), tumor-specific hyperthermia at sublethal (42–47C) or ablative (> 50C) temperatures was generated by illuminating the tumor (or adjacent liver tissue as control) with a 785nm near infrared laser coupled to a clinical fiberoptic catheter. 72h after treatment, normal and tumor tissue were harvested for immunohistochemistry, multi-color flow cytometry, and transcriptomic analysis. Principal component analysis of RNAseq data revealed distinct expression profiles as a function of thermal dose. In particular, sublethal hyperthermia was found to upregulate pathways associated with immunogenic cell death such as the unfolded protein response. It also suppressed non-immunogenic cell death pathways such as apoptosis and upregulated genes associated with the type I interferon response. Both sublethal and ablative hyperthermia doses were associated with an increase in CD8+ cytotoxic T-cell infiltration within the tumors. Paradoxically, ablative hyperthermia was also associated with an increase in the expression of multiple components of the hepatocyte growth factor/cMet pathway. Tumor-specific hyperthermia is associated with transcriptional and microenvironmental modifications that can improve anti-tumor immunity.
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