Hepatocellular Carcinoma Escapes Immune Surveillance through Deceiving Thymus into Recalling and Killing Peripheral Activated CD8+ T Cells

BACKGOUND & AIMS: The role of thymic epithelial cells (TECs) in elimination of self-reactive T cells through presentation of self-antigens is well-established. However, it remains unclear whether TECs can effectively clear hepatocellular carcinoma (HCC)-reactive T cells by presenting HCC-associated antigens. METHODS: HCC nodules and thymuses were harvested from spontaneous and in situ transplanted tumors. Differentially expressed proteins or genes in the aforementioned tissues were determined using liquid chromatograph mass spectrometer (LC-MS) and mRNA transcriptomic sequencing (mRNA-seq). Cell death in histological tissue sections was detected and quantified through the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique. Specific protein expression and immune phenotype were evaluated by multiplex immunofluorescence staining and flow cytometry. RESULTS: In comparison to normal thymuses, there is a significant increase in CD8+ T cell death within the thymuses of HCC model mice. Notably, a substantial portion of these dead cells are peripheral activated T cells homing to the thymus. Mechanistically, TECs did not express tumor-associated antigens by themselves, instead, they captured antigens from HCC cells for antigen presentation. Thymus-homing tumor antigen-specific T cells-initiated activation-induced T cell death (AICD) when they recognized the same antigen presented by TECs. Thymectomy suppressed HCC tumor by redistributing CD8+ T cells into the tumor focus. Importantly, instead of thymectomy, adenosine monophosphate activated protein kinase (AMPK) activator and C-C chemokine receptor type 7 (CCR7) antagonist dramatically decreased immune escape while effectively restrained HCC through curtailing the thymus homing of peripheral activated CD8+ T cells. CONCLUSION: Our findings suggest that HCC deceives thymus into recalling and killing peripheral activated CD8+ T cells. Pharmacological blocking thymus homing of CD8+ T cells via AMPK activation and CCR7 antagonism would be an attractive and promising strategy for HCC prevention and treatment. To investigate the impact of hepatocellular carcinoma (HCC) on thymic gene expression and biological function, we established a diethylnitrosamine (DEN) combined with carbon tetrachloride (CCl4)-induced HCC model in C57BL/6J mice. We then obtained HCC and thymus samples for mRNA sequencing analysis.