# PGE2 Receptor Suppression of cGAS/STING Responses in anti-tumor immunity

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $193,125

## Abstract

Project Summary
The strength of the inflammatory signature in the tumor microenvironment (TME) is a critical determinant of the
host anti-tumor immune response. Type I Interferon (IFN) production by tumor tissue directly or by tumor
associated macrophages and dendritic cells can increase the inflammatory potential of the TME and
significantly increase spontaneous cell mediated anti-tumor responses (e.g. CD8 T and NK). The cGAS/STING
innate immune sensor system has recently been uncovered as a major driver of IFN production in the TME
and this has generated considerable interest in pharmacologic stimulation of cGAS/STING alone and in
conjunction with other immuno-therapies. However, how tumors may evade or minimize cGAS/STING
responses in response to agonists is an open question. We have found that activators of the cGAS/STING
axis trigger a coincident prostaglandin PGE2 response which potently suppresses STING dependent IFN
production through the specific EP3 receptor. This PGE2 autocrine/paracrine negative feedback loop likely
functions to limit the extent of cGAS/STING IFN production both from the tumor tissue itself, and from tumor
associated innate immune cells. This preliminary observation is also notable in light of an extensive tumor
biology literature demonstrating that numerous tumor types can constitutively secrete high levels of PGE2 that
is associated with tumor aggressiveness and poor patient prognosis. Such deleterious effects of tumor
secreted PGE2 may be due in part to suppression of innate immune surveillance by cGAS/STING. The overall
goal of this project is to understand the mechanism of PGE2 production during cGAS/STING responses in
tumors, and to determine whether inhibition of one PGE2 receptor, EP3, can contribute to tumor control in in
vivo pre clinical models. In AIM 1 we will define the pathways governing PGE2 production in primary immune
cells and tumor cell lines and ascertain whether regulation of cGAS/STING by PGE2 /EP3 is a common feature
of tumors from multiple tissue types. In AIM2 we will use established animal tumor models to test the efficacy
of pharmacologically inhibiting the PGE2/EP3 feedback circuit on cGAS/STING activation and IFN responses in
the TME.

## Key facts

- **NIH application ID:** 10115611
- **Project number:** 5R21AI152051-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Darren Perkins
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,125
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115611

## Citation

> US National Institutes of Health, RePORTER application 10115611, PGE2 Receptor Suppression of cGAS/STING Responses in anti-tumor immunity (5R21AI152051-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10115611. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*