The role of MHC class II epitopes in spontaneous and therapeutic immune responses targeting liver cancer

• Applicant: Privatdozent Dr. Thomas Wirth
• Subject Area: Gastroenterology ; Hematology, Oncology ; Clinical Immunology and Allergology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495983343

CD8 T cells are at the forefront of adaptive immunity in the battle against malignant cells. In cancer patients, however, CD8 T cells fail to eliminate cancer cells and enter a state of exhaustion that prevents cancer clearance. In this context MHC class II epitopes which activate CD4 T cells play a major role in supporting CD8 T cell immune responses and driving CD8 T cell differentiation towards an effector phenotype with potent cytolytic properties. In the absence of CD4 T cells, CD8 T cell expansion is reduced in size and poised towards a differentiation state with insufficient recall properties, termed "helpless CD8 T cells". Since the magnitude of antitumoral immune responses is in general low, the contribution of CD4 T cells to CD8 responses is harder to determine than in responses to acute infection. Recently, MHC class II epitopes have been shown to enhance CD8 T cell expansion and tumor infiltration in sarcoma. Interestingly, this effect was independent of surface MHC class II expression by the tumor. This fact implies that tumor antigens which harbor immunogenic MHC class II epitopes are taken up by dendritic cells and presented on the dendritic cells' MHC class II molecules to CD4 T cells. How CD4 T cells direct CD8 T cells towards the tumor and favor oncolysis, however, remains largely elusive. Furthermore, it remains unclear whether this role of CD4 help is specific for sarcoma or applicable to other tumor entities as well. In our research project we aim at elucidating the role of CD4 T cell help in spontaneous immune responses and immunotherapy of hepatocellular carcinoma. For this purpose, our group has developed subcutaneous and autochthonous liver cancer models, defined a number of MHC class I and II epitopes and developed several potent cellular vaccination strategies. In contrast to the data published on sarcoma, we have demonstrated elimination of liver cancer in mice using vaccinations with a single, MHC class I-specific CD8 T cell epitope in the absence of CD4 T cell help. These CD8 T cell responses were induced with a patented, heterologous cancer vaccine that employs a dendritic cell priming followed by a booster immunization with agonistic, costimulatory antibodies. Using this established prime-boost regimen we will analyze the role of CD4 T cell help in spontaneous, adaptive immune responses targeting liver cancer as well as therapeutic T cell vaccines and try to resolve the conflicting results regarding MHC class II epitopes in tumor therapy. We will furthermore extend our studies to other immunotherapies and clarify the role of MHC class II epitopes in checkpoint inhibitor therapies of hepatocellular carcinoma. Finally, using our vaccination technology we will generate a transcriptome profile of CD4 T cell help in CD8 T cells and analyze key molecules and pathways involved in CD4 T cell help.

• DFG Programme: Research Grants