Harnessing T cell immunity for the prevention and treatment of liver cancer

Abstract

Hepatocellular carcinoma (HCC) accounts for more than 80% of all diagnosed cases of liver cancer which is a major cause of cancer related fatalities worldwide. With few improvements in the survival rates during the last decades, prevention of HCC is key in reducing its burden globally. Infection with hepatitis B virus (HBV) remains the main etiological risk factor for developing HCC whilst in HBV patients co-infected with hepatitis D virus (HDV), the risk of developing HCC is triplicated due to the accelerated liver disease progression. In studies I and II, we aimed to develop a therapeutic vaccine for chronic HBV and HDV, as a preventive strategy for HCC. In study III, we sought to unlock novel T cell-based immunotherapies, as treatment for advanced HCC through isolation of neoantigen-driven T cell receptors (TCRs).

In study I, we show that a homologous preS1-HDAg DNA-based vaccine strategy was able to elicit robust T cell responses to HBV and HDV antigens and entryinhibiting antibodies that could limit HBV monoinfection in liver-humanized mice. In study II, a heterologous DNA prime and protein boost preS1-HDAg vaccine strategy improved immunogenicity and could circumvent the HBV-induced tolerance present in the chronically infected host. Additionally, vaccine-induced antibodies protected liver-humanized mice against a chronic HBV/HDV coinfection and importantly they could protect HBV infected human-liver mice from HDV superinfection. In study III, we studied the cancer-specific T cell responses in patients with HCC, and we could detect T cell reactivity against mutated neoantigens in 4 out of 7 screened HCC patients. We isolated (putative) tumorreactive TCRs for further evaluation of their expression and specificity. Neoantigen-specific TCRs could be utilized to genetically redirect a substantial quantity of T cells against tumor cells, thus offering a potential new treatment for advanced HCC.

Taken together, as we continue to unravel the dynamics of the immune system and refine therapies in the context of chronic diseases, this thesis illuminates two promising T cell avenues in the form of active and passive T cell immunotherapy and provides novel insights in the development of preventive and therapeutic tools aiming at combatting liver cancer.