Periodic Reporting for period 1 - Tumour T cells (The fate and therapeutic potential of human neoantigen-specific T cells)
Reporting period: 2021-09-01 to 2023-08-31
Cancer is a leading global health challenge and second highest cause of death worldwide. Despite advancements in treatment, many patients still do not respond effectively to cancer immunotherapies, which are designed to harness the body's immune system to fight cancer. Immunotherapy holds great promise, but its limited success rate means there's a pressing need for better strategies to identify effective targets and overcome the mechanisms that make cancer resistant to treatment.
This research aimed to investigate cancer-specific T cells, which are immune cells that can recognize and attack cancer cells, exploring their potential in treating cancer. It also focused on understanding why CD8 T cells, which are crucial for killing cancer cells, often fail in cancer patients. The study sought to identify immunogenic targets by examining cancer antigens—substances that provoke an immune response—in different conditions, including those with acute inflammation and without inflammation. Additionally, the research analyzed the variety of T-cell receptors (TCRs) on tumor-specific CD8 T cells to understand their diversity and potential in fighting cancer.
By addressing these objectives, the research aimed to develop more effective cancer immunotherapies, ultimately benefiting patients by increasing treatment success rates and providing new hope in the fight against cancer.
This research aimed to investigate cancer-specific T cells, which are immune cells that can recognize and attack cancer cells, exploring their potential in treating cancer. It also focused on understanding why CD8 T cells, which are crucial for killing cancer cells, often fail in cancer patients. The study sought to identify immunogenic targets by examining cancer antigens—substances that provoke an immune response—in different conditions, including those with acute inflammation and without inflammation. Additionally, the research analyzed the variety of T-cell receptors (TCRs) on tumor-specific CD8 T cells to understand their diversity and potential in fighting cancer.
By addressing these objectives, the research aimed to develop more effective cancer immunotherapies, ultimately benefiting patients by increasing treatment success rates and providing new hope in the fight against cancer.
We aimed to understand and enhance the CD8 T cell response to cancer antigens. For this, we used the highly immunogenic SV40 large T antigen (Tag), which successfully led to tumor rejection under various conditions. We further investigated the role of inflammation in T cell responses using a new triple-transgenic mouse model. Continuous expression of Tag without inflammation resulted in T cell dysfunction and tumor growth, mirroring some aspects of human cancer.
We next explored the fate of tumor-specific T cells in the tumor microenvironment. Using an autochthonous cancer model, we discovered that tumor-specific CD8 T cells became dysfunctional over time. Our detailed analyses revealed that these T cells had a gene signature similar to exhausted T cells, offering insights into why they failed to combat tumors effectively. Moreover, tolerant T cells downregulated their TCR which contributed to their dysfunction and lack of tumor recognition.
In our final work package, we tested the potential of cancer antigens for immunotherapy. While a vaccine approach alone was insufficient to re-activate T cells, combining it with other therapies showed promise in inducing tumor rejection. We identified new therapeutic targets and developed a sophisticated mouse model that replicates human tumor environments, providing a robust system for testing cancer treatments
We next explored the fate of tumor-specific T cells in the tumor microenvironment. Using an autochthonous cancer model, we discovered that tumor-specific CD8 T cells became dysfunctional over time. Our detailed analyses revealed that these T cells had a gene signature similar to exhausted T cells, offering insights into why they failed to combat tumors effectively. Moreover, tolerant T cells downregulated their TCR which contributed to their dysfunction and lack of tumor recognition.
In our final work package, we tested the potential of cancer antigens for immunotherapy. While a vaccine approach alone was insufficient to re-activate T cells, combining it with other therapies showed promise in inducing tumor rejection. We identified new therapeutic targets and developed a sophisticated mouse model that replicates human tumor environments, providing a robust system for testing cancer treatments
The project's findings have significant socio-economic and societal implications. By uncovering mechanisms that enhance the immune response against cancer, particularly through the identification and reactivation of dysfunctional T cells, our research paves the way for more effective and personalized immunotherapy treatments. This has the potential to reduce healthcare costs associated with prolonged and less effective cancer treatments, improve patient survival rates, and enhance quality of life. Additionally, the development of advanced mouse models that closely replicate human tumor environments accelerates the pace of cancer research, potentially leading to advancements in treatment options. These improvements in cancer therapy not only benefit patients and their families but also contribute to the broader goal of reducing the global cancer burden, fostering healthier communities, and improving societal well-being.