ERK1/2 signaling regulates the immune microenvironment and macrophage recruitment in glioblastoma.

Marine Lottin,Christophe Louandre,Thomas Lhossein,Corinne Godin,Claire Lailler,Bruno Chauffert,Zuzana Saidak,Antoine Galmiche,Jean-Marc Constans,Mony Chenda Morisse

doi:10.1042/bsr20191433

Abstract

The tumor microenvironment is an important determinant of glioblastoma (GBM) progression and response to treatment. How oncogenic signaling in GBM cells modulates the composition of the tumor microenvironment and its activation is unclear. We aimed to explore the potential local immunoregulatory function of ERK1/2 signaling in GBM. Using proteomic and transcriptomic data (RNA seq) available for GBM tumors from The Cancer Genome Atlas (TCGA), we show that GBM with high levels of phosphorylated ERK1/2 have increased infiltration of tumor-associated macrophages (TAM) with a non-inflammatory M2 polarization. Using three human GBM cell lines in culture, we confirmed the existence of ERK1/2-dependent regulation of the production of the macrophage chemoattractant CCL2/MCP1. In contrast with this positive regulation of TAM recruitment, we found no evidence of a direct effect of ERK1/2 signaling on two other important aspects of TAM regulation by GBM cells: (1) the expression of the immune checkpoint ligands PD-L1 and PD-L2, expressed at high mRNA levels in GBM compared with other solid tumors; (2) the production of the tumor metabolite lactate recently reported to dampen tumor immunity by interacting with the receptor GPR65 present on the surface of TAM. Taken together, our observations suggest that ERK1/2 signaling regulates the recruitment of TAM in the GBM microenvironment. These findings highlight some potentially important particularities of the immune microenvironment in GBM and could provide an explanation for the recent observation that GBM with activated ERK1/2 signaling may respond better to anti-PD1 therapeutics.

Highlights

Glioblastoma (GBM) is the most common primary central nervous system malignancy in adults
Using proteomic and transcriptomic data (RNA seq) available for GBM tumors from The Cancer Genome Atlas (TCGA), we show that GBM with high levels of phosphorylated ERK1/2 have increased infiltration of tumor-associated macrophages (TAM) with a non-inflammatory M2 polarization
These findings suggested the existence of some form of functional uncoupling between epidermal growth factor receptor (EGFR) and ERK1/2 in GBM cells and supported the existence of a distinct subset of GBM tumors characterized by high levels of phospho-ERK1/2

Summary

Introduction

Glioblastoma (GBM) is the most common primary central nervous system malignancy in adults. In vitro studies exploring the regulation and function of the ERK1/2 kinases, an essential downstream target of the RTK, have reported the role of ERK1/2 signaling in the regulation of GBM cell proliferation, invasion, apoptosis, tumor metabolism, and multiple other facets of tumor cell physiology [4]. Despite this strong rationale, Phase II/III clinical trials aiming to target RTKs, such as the EGFR, have been negative. This has led to skepticism regarding the interest of therapeutic strategies directed against oncogenic signaling in GBM [5]

Objectives

Methods

Results

Conclusion