# Novel mechanisms regulating PD-1 signaling and function

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $405,000

## Abstract

ABSTRACT
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.

## Key facts

- **NIH application ID:** 9948547
- **Project number:** 5R01AI125640-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Adam Mor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2016-06-20 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948547

## Citation

> US National Institutes of Health, RePORTER application 9948547, Novel mechanisms regulating PD-1 signaling and function (5R01AI125640-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9948547. Licensed CC0.

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