Beyond checkpoint inhibitors: Natural killer cells limiting antitumor T cell immunity in hepatocellular carcinoma
Final Report Abstract
The development of new therapeutic strategies for patients with chronic HBV infection and HCC is of high clinical importance. Addressing metabolic checkpoints is a new promising immunotherapeutic approach to revive exhausted antiviral and antitumour CD8+ T cells and to boost immune responses. Targeting cholesterol metabolism by in vitro ACAT inhibition enhanced antiviral and antitumour cytokine production of human CD8+ and CD4+ T cells from blood, liver and tumour. This increased functionality was associated with an enhanced proliferation, lipid raft formation and TCR signalling. Future work will have to further determine the mechanisms behind the enhanced T cell functionality and TCR signaling, e.g. changes in the formation of the immunological synapse, lipid raft structure and lipid and fatty acid metabolism. Moreover, our preliminary data suggested an increased TCR affinity after treatment with ACAT inhibitors. Immune checkpoint blockade has shown promising results for the treatment of various tumours; however, not all patients respond to these therapies and a multipronged approach will be necessary to increase response rates. An exhausted, PD1high phenotype of CD8+ T cells is associated with reduced lipid rafts. Combining in vitro or in vivo PD-1 blockade with in vitro ACAT had a complementary effect and could be superior to PD-1 blockade alone in rescuing HBV- and HCC-specific CD8+ T cell functionality. Future work will be necessary to determine predictors to identify patients that are likely to respond to ACAT inhibition, e.g. using their cholesterol profile and lipid raft expression at baseline. In conclusion, we could show that ACAT inhibitors, capable of re-programming cholesterol metabolism to enhance lipid raft formation, could rescue immediate effector function in HBV- and HCC-specific T cells. Synergism with PD-1 blockade suggests this may be a promising new therapeutic approach to improve current immunotherapeutic strategies.
