# Atherosclerosis, Prostaglandin Inhibition and Checkpoint Blockade

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $649,492

## Abstract

Project Summary
Checkpoint blockade targeting the Programmed cell Death (PD-1) / PD-Ligand1 pathway has proven effective
in a range of cancers by releasing a restraint on cytotoxic T lymphocytes (CTLs). However, a concern has
been that this very mechanism might predispose to cardiovascular and autoimmune diseases. Anecdotal
evidence of a cardiovascular hazard has emerged and abundant data point to exacerbation of atherosclerosis
in mice consequent to Pd-1 deletion. Recently, the generation of prostaglandin (PG) E2 by the sequential
action of the cyclooxygenase (COX)-2 and microsomal PGE synthase enzymes, acting via its E prostanoid
(EP) receptors, EP2 and EP4, has been shown also to promote lymphocyte exhaustion. This raises the
possibility of a combinatorial approach to cancer with nonsteroidal anti-inflammatory drugs (NSAIDs) and
checkpoint inhibitors. However, COX-2 inhibition alone confers a cardiovascular risk and may exacerbate one
consequent to checkpoint blockade. Here, we address this possibility, first seeking to build on our preliminary
data in mouse and human cells that there appears to be a bidirectional regulatory interaction between the PD-1
and PG pathways. Using pharmacological and genetic approaches, we will determine whether modulation of
PGE2 alters lymphocyte phenotype and function and how regulation of PD-1 may influence the PGE2
biosynthetic response pathway both in mouse and human cells. We will use atherogenesis in the mouse as a
surrogate for cardiovascular risk in humans (as it proved to be for NSAIDs and as it correlates to date with
checkpoint inhibitors) and determine if deletion of Cox-2 accelerates and exacerbates the immuno-
inflammatory atherosclerotic phenotype consequent to Pd-1 deletion. We will then determine whether
alternative approaches to PGE2 suppression (deletion of the microsomal PGE Synthase [mPGES] – 1; EP
blockade or inhibition of either enzyme restricted to myeloid cells) might limit or avoid the acceleration of
atherosclerosis consequent to deletion of Pd-1. These studies will combine differential perturbations of the PG
pathway in cells obtained from melanoma patients receiving PD-1 blockade, novel mouse models, state of the
art immunophenotyping, single cell transcriptomics and mass-spectrometry based lipidomic substrate imaging
and product analysis defining atherosclerotic lesions to understand a potentially serious risk of combining
NSAIDs with checkpoint inhibitors. We shall also explore novel alternative approaches to suppressing PGE2
that might conserve the anti-cancer efficacy and minimize the cardiovascular risk of combinatorial therapy.

## Key facts

- **NIH application ID:** 9842568
- **Project number:** 5R01HL141912-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** GARRET A FITZGERALD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $649,492
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842568

## Citation

> US National Institutes of Health, RePORTER application 9842568, Atherosclerosis, Prostaglandin Inhibition and Checkpoint Blockade (5R01HL141912-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842568. Licensed CC0.

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