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Courtney M. Smith

Courtney Smith PDPT19
Predoctoral Fellowship in Pharmacology/Toxicology, 2019 Yale University

Understanding TIM3 Signaling


Reactivating the immune response against cancer cells by immune checkpoint blockade (ICB) has revolutionized cancer treatment. This therapeutic strategy blocks the interaction between immune cell inhibitory receptors and their ligands, releasing the inhibitory “brake” on the immune system to allow it to target and kill tumor cells. For example, therapies targeting the PD-1/PDL1 axis have been shown to reactivate immune responses to cancer. However, the majority of patients fail to respond to ICB, and those that do respond can develop resistance and progress. 48 Therefore, new strategies are needed to overcome these current limitations to ICB therapy. A potential strategy is to target some of the many additional checkpoint receptors. One such target is TIM3, a receptor that – like PD-1 – is expressed on dysfunctional T cells in the tumor microenvironment. In mouse models, combined PD-1 – TIM3 blockade is synergistic, supporting the potential of TIM3 blockade. However, a major challenge for TIM3 – and for many other immune checkpoint receptors – is the lack of understanding of how these receptors signal and are regulated by ligand. The goal of this project is therefore to understand how TIM3 modulates T cell signaling, how TIM3 is regulated by its putative ligand(s), and further, to improve the translation of candidate TIM3 therapies to the clinic. To address these questions, putative TIM3- ligand interactions were validated using biophysical approaches, and cellular signaling assays evaluated their biological relevance. Additionally, therapeutic antibodies will be assessed to interrogate relevant ligand-binding sites. Ultimately, this project will provide new insight into the mechanism of a novel target for ICB, aid the design of more mechanistically focused therapies, and help with stratification of the clinical utility of TIM3 therapies currently in early stage clinical trials. Moreover, this project will more generally inform the field of signaling by T cell co-receptors

I am very grateful to have received a PhRMA Foundation Predoctoral Fellowship. Receiving this award has provided me the opportunity to pursue my thesis research in immune co-receptor signaling, a new biological area for our lab. The funding from this award has been instrumental in allowing me to complete key experiments to drive my project forward. Furthermore, this award has provided a network and resources to help me begin a career in the pharmaceutical industry after graduate school. The support from the PhRMA Foundation has had a positive and lasting impact on my research, and has been an invaluable part of my graduate school experience.

Courtney M. Smith