Emerging Role of EGFR Mutations in Creating an Immune Suppressive Tumour Microenvironment

Abstract

Several types of tumours overexpress the Epidermal Growth Factor Receptor (EGFR) in either wild type or mutated form. These tumours are often highly aggressive and difficult to treat. The underlying mechanisms for this phenomenon have remained largely unresolved, but recent publications suggest two independent mechanisms that may contribute. According to one line of research, tumours that overexpress the EGFR grow autonomously and become “addicted” to growth factor signalling. Inhibition of this signal using EGFR inhibitors can, therefore, induce cell death in tumour cells and lead to tumour shrinkage. The other line of research, as highlighted by recent findings, suggests that the overexpression, specifically of mutant forms of the EGFR, may create an immune-suppressive and lymphocyte depleted microenvironment within tumours. Such a lymphocyte depleted microenvironment may explain the resistance of EGFR overexpressing cancers to tumour therapies, particularly to check-point inhibitor treatments. In this article, we discuss the recent data which support an immune modulatory effect of EGFR signalling and compare these published studies with the most recent data from The Cancer Genome Atlas (TCGA), in this way, dissecting possible underlying mechanisms. We thereby focus our study on how EGFR overexpression may lead to the local activation of TGFβ, and hence to an immune suppressive environment. Consequently, we define a novel concept of how the mitogenic and immune modulatory effects of EGFR overexpression may contribute to tumour resistance to immunotherapy, and how EGFR specific inhibitors could be used best to enhance the efficacy of tumour therapy.

Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

“…[ 29 ] The TME within EGFR‐mutation driven lung tumors has been depicted as having a lack of anti‐tumor lymphocytes and an accumulation of immune‐suppressive factors (cells and cytokines). [ 30 ] One recent study revealed that there is a positive correlation between EGFR overexpression and significant lack of cytotoxic CD8 + T cells in TME. [ 31 ] Moreover, it was revealed that EGFR mutations could actively promote CD8 + T cell apoptosis more than wildtype non‐small cell lung cancer patients.…”

Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need

“…With some exceptions within the group of ex20ins, EGFR-TKIs seem to be the best treatment option for uncommon EGFR mutations, and recent data confirm a modest activity of ICIs [19,107]. This is probably due to the tumor immune microenvironment of EGFR mutant NSCLC, which is associated with uninflamed characteristics, low PD-L1 (programmed death-ligand-1) expression/CD8+ TILs (Tumor-infiltrating lymphocytes), and a low tumor mutational burden (TMB) [108,109]. Interestingly, some patients with a history of smoking and high PD-L1 expression [110], despite harboring an EGFR mutation, may benefit from treatment with ICIs, especially patients harboring uncommon mutations [66,74,110].…”

“…EGFR mutant NSCLC, which is associated with uninflamed characteristics, low PD-L1 (programmed death-ligand-1) expression/CD8+ TILs (Tumor-infiltrating lymphocytes), and a low tumor mutational burden (TMB) [108,109]. Interestingly, some patients with a history of smoking and high PD-L1 expression [110], despite harboring an EGFR mutation, may benefit from treatment with ICIs, especially patients harboring uncommon mutations [66,74,110].…”