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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI125640-01
Application #
9158876
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Mallia, Conrad M
Project Start
2016-06-20
Project End
2021-05-31
Budget Start
2016-06-20
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$423,750
Indirect Cost
$173,750
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Strazza, Marianne; Azoulay-Alfaguter, Inbar; Peled, Michael et al. (2017) PLC?1 regulates SDF-1?-induced lymphocyte adhesion and migration to sites of inflammation. Proc Natl Acad Sci U S A 114:2693-2698
Sandigursky, Sabina; Silverman, Gregg J; Mor, Adam (2017) Targeting the programmed cell death-1 pathway in rheumatoid arthritis. Autoimmun Rev 16:767-773