# PAG is a novel target in immunotherapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $583,390

## Abstract

PROJECT ABSTRACT
Immune checkpoint therapies block inhibitory receptors on T cells to augment anti-tumor immune responses.
The Programmed cell Death-1 (PD-1) pathway is a critical inhibitory checkpoint for T cells, and antibodies
blocking PD-1 promote immune-mediated identification and clearance of malignant cells. Cancer
immunotherapies, including anti-PD-1 antibodies, represent a powerful therapeutic paradigm because they are
applicable to a wide variety of tumors and can produce durable clinical responses. Unfortunately, only a
fraction of patients demonstrates clinical benefit from current agents. As such, there is an urgent need to
develop therapeutics that more effectively target PD-1 signaling as well as other checkpoint inhibitors. We
have employed phosphoproteomic protocol to identify proteins that regulate downstream signaling of PD-1.
With this approach, we identified the protein PAG as an effector of PD-1 immune checkpoint signaling. We
have discovered that PAG is required for PD-1 signaling and inhibition of T cell function and our preliminary
genetic and biochemical studies confirm PAG as a target for reversing T cell inhibition. The immediate goal of
this proposal is to validate PAG as checkpoint inhibitor candidate. Our long-term goal is to translate our
findings and to generate novel immunotherapies for patients with malignancies. We will accomplish these
goals with the following aims: Aim 1. Define the mechanism by which PD-1 induces PAG phosphorylation to
promote immune checkpoint activation. Using high resolution microscopy, we will determine how PD-1 and
PAG cluster at the immunological synapse. Using mutagenesis, we will define the requirement for specific
tyrosine within the cytoplasmic region of PAG for PD-1 function and immune synapse clustering. Aim 2. To
assess PAG-mediated immune inhibitory potential, in vivo. We will assess tumor growth in syngeneic models
using PAG knockout mice. Aim 3. To develop anti-PAG functional antibodies. We will develop strategies to
target PAG in vivo. Together, these studies will uncover the mechanism by which PAG mediates inhibitory
signals in T cells and its value as a novel target for immune checkpoint blockade.

## Key facts

- **NIH application ID:** 10120348
- **Project number:** 1R01AI150597-01A1
- **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:** $583,390
- **Award type:** 1
- **Project period:** 2020-09-17 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120348

## Citation

> US National Institutes of Health, RePORTER application 10120348, PAG is a novel target in immunotherapy (1R01AI150597-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120348. Licensed CC0.

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