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.
Highlights
Tumour immunotherapy has made tremendous progress in recent years
As the absence of tumour infiltrating lymphocytes (TILs), like the cytotoxic CD8 T-cells, is a well-established marker for poor anti-tumour immune responses following immune check-point inhibitors (ICIs) treatments [3], these findings suggested that a lack of CD8 T-cells within mutated Epidermal Growth Factor Receptor (EGFR) overexpressing tumours may explain why such types of tumours showed only poor responses to ICI treatments
Given the positive correlation between EGFR mutations and “lymphocyte depletion” phenotype in the recent pan-cancer analysis of The Cancer Genome Atlas (TCGA) [37], we performed a comprehensive TCGA-based analysis of the tumour microenvironment (TME) associated with EGFR mutations, with a particular focus on lung adenocarcinomas (LUADs)
Summary
Tumour immunotherapy has made tremendous progress in recent years. Many types of tumours that were considered untreatable only a few years ago currently show promising clinical response rates upon treatment with biologicals, such as monoclonal antibodies targeting so-called immune check-point inhibitors (ICIs), like PD-1/PD-L1 and CTLA-4 [1,2]. As the absence of tumour infiltrating lymphocytes (TILs), like the cytotoxic CD8 T-cells, is a well-established marker for poor anti-tumour immune responses following ICI treatments [3], these findings suggested that a lack of CD8 T-cells within mutated EGFR overexpressing tumours may explain why such types of tumours showed only poor responses to ICI treatments Taken together, these recent studies suggested a rather pronounced immune-modulatory role of EGFR when it was overexpressed, for mutant forms of the EGFR. Given the positive correlation between EGFR mutations and “lymphocyte depletion” phenotype in the recent pan-cancer analysis of The Cancer Genome Atlas (TCGA) [37], we performed a comprehensive TCGA-based analysis of the TME associated with EGFR mutations, with a particular focus on lung adenocarcinomas (LUADs) To this end, we aimed to provide insights into underlying immunotherapy-resistance mechanisms by validating the effect of EGFR mutation types on the immune landscape using a transcriptome-based in silico analysis. Based on the insight gained from this study, we will in the following discuss the findings of different studies and suggest a common mechanism of how the overexpression of mutant forms of the EGFR may contribute to the creation of an immune suppressive tumour microenvironment and the observed “lymphocyte depletion” phenotype
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