Diacylglycerol Activation of T-Cell Receptor Signaling for Cancer Immunotherapy
Abstract
We have accomplished the goals and milestones outlined in this proposal, which has resulted in 8 peer-reviewed publications, 35 invited talks, and 9 conference abstracts to disseminate our research findings. As part of our research efforts, multiple graduate students received vital career development opportunities at prestigious national meetings. Our findings have impacted fields outside of chemistry and cancer immunology by showing the lipid biology field that chemical biology approaches can provide fundamental information on how lipid kinases impart metabolic and signaling specificity in cells. We generated preclinical data in a melanoma mouse model that ritanserin in combination with anticancer drugs can significantly increase survival compared with delivery of either agent alone. In a small cohort of mice, the combination showed complete resolution of their tumor beyond termination of therapy, and we observed increased CD8+ T cell infiltration in treated mice compared with controls. We discovered new lipid biomarkers for DAG kinase function in T cells. We also developed new chemistry to improve the potency of ritanserin by targeting novel regions of the DAG kinase-alpha active site through a covalent mechanism of inhibition. We believe our studies and findings have broader impacts in society by continuing to show our commitment to drug fat metabolism for immuno-oncology. Working with fats, especially as signaling molecules, is challenging and we are enthusiastic about educating the public and providing tools for the wider scientific community to study these metabolites.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2020
- Accession Number
- AD1166350
Entities
People
- Ku-lung Hsu
Organizations
- University of Virginia