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. Overall design: 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.