Decoding and targeting the PGE2-MEF2A axis in tumor-associated macrophages

Introduction

Inflammation is a complex spectrum of processes whose outcomes range from cell killing to tissue regeneration. In this context, a major goal in immune oncology is the development of treatments that stimulate cytotoxic immunity while limiting repair in the tumor microenvironment (TME). These approaches have the potential to synergize with available immunotherapies and provide benefit to otherwise resistant patients.

Background

Pancreatic cancer is a largely incurable disease, in which aberrant inflammation and profound immune suppression conspire to sustain disease initiation, progression, and immune escape. Accumulating evidence supports the view that tumor-associated macrophages (TAMs) are key orchestrators of the balance between cytotoxicity and regeneration, and thus represent promising therapeutic targets in pancreatic cancer.

Objectives

In MEFHISTO, we aim at elucidating the following:

1. The molecular control of the PGE2-MEF2A axis.
2. The functional implications of this pathway.
3. The therapeutic potential of targeting the PGE2-MEF2A axis.

This newly described pathway enables selective control of inflammatory gene expression in macrophages.

Methodology

By combining advanced genomic analyses in human samples, functional experiments in preclinical models, and mechanistic studies in key cell types, this proposal will expand our knowledge of the organizing principles of innate immune responses in tumors.

Expected Outcomes

The ensuing results may lead to novel combinatorial treatments for diseases, such as pancreatic cancer, that are refractory to immunotherapy.