Ligand Expression on Tumor-Associated Vasculature Orchestrates CD8+ T-Cell Infiltration into Tumors
Abstract
The opportunity to be awarded a Horizon Fellowship will bring me one step closer to achieving my career goal of becoming a successful, independent investigator at the forefront of melanoma research. I strive to have my work directly impact how we treat patients with melanoma. The proposed research aims to improve clinical responses to various therapeutic strategies frequently used for the treatment of melanoma. It will also provide a solid foundation for the discovery of new therapeutic approaches designed to improve patient outcome. These studies will have important implications for our active duty Service members given that they have an increased incidence rate of melanoma compared to the general population. Integral to the proposed researcher development plan is the training that I will obtain within the laboratory of my primary mentor, Dr. Vic Engelhard. Dr. Engelhard is a nationally and internationally recognized leader in melanoma and immunology research. His highly collaborative lab consists of a superb group of postdoctoral fellows, predoctoral trainees, and research colleagues that serve as an excellent source of support. The lab holds weekly meetings and journal clubs that focus specifically on the role of the immune system and its important contributions to the melanoma tumor microenvironment. My co-mentors and collaborators, Dr. Craig Slingluff and Dr. Kim Kelly, provide me with the tools and resources necessary to have a multidisciplinary impact on how we diagnose and treat melanoma patients. An intact, yet tolerant, immune system is important for protecting the body against disease, ranging from fighting a common cold or bacterial infection to battling cancer. The concept of cancer immunotherapy involves harnessing one s own immune system to help fight tumor progression. Infiltration of T cells into tumors is associated with improved patient survival. This is due to the fact that T cells can recognize tumor-specific antigens that allow them to directly attack and kill tumor cells with high efficiency and specificity. While immunotherapies have had some success in treating a subset of melanoma patients, their efficacy is often limited by the failure of T cells to efficiently traffic to and enter tumors. A well-established immunotherapy used in the clinic to treat melanoma patients is called adoptive T cell transfer (ACT) therapy. ACT therapy involves isolating a patient s own T cells, expanding them, and reinfusing them back into the patient with the goal of increasing the numbers of T cells available to attack tumor cells. Unfortunately, however, an incredibly small number of T cells actually infiltrate into tumors. Given that the presence of infiltrating T cells is associated with a good prognosis, it is necessary that we gain a better understanding of the mechanisms controlling T cell entry into tumors. It is well established that activated T cells traffic from lymph nodes through the bloodstream to get to peripheral solid tumors within the body. Once at the tumor site, a series of molecules displayed on the vasculature interact with T cells to facilitate their exit from the bloodstream and entry into the tumor. The proposed research aims to understand how these molecules promote T cell infiltration and how we can potentially manipulate these molecules to allow the vasculature to become more permissible to T cell entry. Furthermore, as tumors progress, the role of the microenvironment becomes complex. Advanced disease can be associated with an immunosuppressive microenvironment, where different cell types within the tumor function to inhibit T cell-mediated immunity. Therapies that disrupt immunosuppression are another current strategy used to treat patients with melanoma. A major objective of the proposed research tests the hypothesis that interfering with immunosuppression will help increase T cell entry into tumors. This work will have immediate clinical impact given that agents
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610299
Entities
People
- Ashley Wilson
Organizations
- United States Army
- University of Virginia