Immune checkpoint therapies block inhibitory receptors on T cells in efforts to augment anti-tumor immune responses. The Programmed death-1 (PD-1) pathway is a critical inhibitory checkpoint in T cells and antibodies blocking PD-1 promote immune-mediated identification and clearance of malignancies. Cancer immunotherapies, like anti-PD-1 antibodies, represent a paradigm shift in cancer treatment because they do not target the tumor cell directly. Instead, by harnessing the immune system, anti-PD-1 therapies can elicit durable clinical responses in multiple tumor types, including long-term remissions. Unfortunately, the benefit of anti-PD-1 therapy is realized in only a fraction of patients. As such, developing additional therapeutics that can better inhibit this pathway will extend the benefit of this approach to many additional patients. To achieve this goal, a deeper insight into the signaling events downstream of PD-1 and characterization of the molecular mechanism(s) by which PD-1 exerts its inhibitory effect is critical. Toward this end, we have taken an unbiased approach to identify novel targets in the PD-1 checkpoint pathway. We used advanced mass spectrometry to identify new signaling pathways downstream of PD-1. Using this system, we identified multiple candidates that we categorized into two groups: promoters or suppressors of PD-1 functions. Excitingly, we found that silencing PD-1 promoters, and not suppressors, with RNAi abrogated the inhibitory effects of PD-1. We now seek to elucidate the mechanisms by which these proteins affect PD-1 function and determine their suitability as either targets for drug discovery or biomarkers for PD-1 treatment with three specific aims: In the first aim we will confirm that the interaction between PD-1 and the newly discovered promoters is direct in primary human T cells. In order to study the physical interactions, we will utilize high-resolution microscopy. We will incorporate an in vivo mouse model of cancer into our studies, with the goal of establishing a role for our candidates in tumor progression/regression. In the second aim we will further characterize the functional role of PD-1 suppressors in primary human T cells and measure cytokine secretion, proliferation, and cellular adhesion in response to stimulation. In the third aim we will investigate the subcellular distribution of PD-1 modulators and measure their ability to form mature immunological synapses. Taken together, the execution of these aims will help define a mechanistic understanding of PD-1 function to guide the development of improved cancer immunotherapies and potential biomarkers of anti-PD-1 responses.
Our immune system is designed to protect us not just from infection, but also to fight cancer; activating the immune system with different drugs is a new approach to treat patients with different malignancies. This project will study PD-1, a protein that plays a role in regulating lymphocytes, a type of white blood cell that is a key component in immune system regulation. A better understanding of this protein, its function and action should permit the identification of critical components that can serve as targets for the development of new therapies for cancers.
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