Abstract
Epidermal Growth Factor Receptor (EGFR) antagonists were one of the first anti-cancer treatments developed targeting a Receptor Tyrosine Kinase. However, the underlying mode of action of how EGFR antagonist application can explain its clinical efficacy in different types of cancers remains largely unresolved. Numerous findings have suggested that a substantial portion of the effects attributed to EGFR antagonist treatment might not be based on direct influence on the tumor itself. Instead it may be based on indirect effects, potentially mediated via the immune system. In this review the role of the EGFR for the functioning of the immune system is discussed, alongside how EGFR antagonist treatment could be impacting tumor growth by blocking macrophage and FoxP3-expressing regulatory CD4+ T cell function. Based on these findings, we consider implications for current treatment schemes and suggest novel approaches to improve the efficacy of EGFR antagonist treatment in the future. Finally, we propose potential ways to improve EGFR antagonists, in order to enhance their clinical efficacy whilst diminishing unwanted side effects.
Highlights
The underlying mode of action of how Epidermal Growth Factor Receptor (EGFR) antagonist application can explain its clinical efficacy in different types of cancers remains largely unresolved
Numerous findings have suggested that a substantial portion of the effects attributed to EGFR antagonist treatment might not be based on direct influence on the tumor itself
The clinical efficacy of EGFR antagonists in cancer treatment was an unexpected finding, as the EGFR is ubiquitously expressed throughout the human body and not itself an oncogene
Summary
It has been well-established that the EGFR is expressed on many different haematopoietic cell types and that its expression is of central importance for their functioning These cell types include macrophages (Scholes, 2001; Lanaya et al, 2014), monocytes (Chan et al, 2009), plasma cells (Mahtouk et al, 2005), and certain T cell subsets such as effector CD4 T cells and FoxP3-expressing regulatory CD4 T cells (Tregs) (Zaiss et al, 2013). Other suppressive cell types are found in the tumor microenvironment, including regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). These cells dampen the anti-tumor immune response by interacting with cells such as NK cells, T cells, and dendritic cells (DC) (Zou, 2006; Ostrand-Rosenberg and Sinha, 2009). It is reasonable to assume that EGFR antagonist interference with any of these leukocytes’ function may advantageously contribute to the clinical efficacy of anti-tumor treatments
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