EGFR-mediated tumor immunoescape: The imbalance between phosphorylated STAT1 and phosphorylated STAT3

Abstract

The epidermal growth factor receptor (EGFR) supports the escape of malignant cells from immunosurveillance by inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) while promoting that of STAT3. We have recently demonstrated that protein tyrosine phosphatase, non-receptor type 11 (PTNP11, best known as SHP2), a phosphatase that operates downstream of EGFR, is responsible for the dephosphorylation of active STAT1 and for the inhibition of the antigen-processing machinery (APM), hence favoring tumor immunoescape. Thus, EGFR signaling may skew the tumor microenvironment to suppress cellular immune responses.

Keywords: APM; EGFR; SHP2; immunoescape; immunotherapy; pSTAT1; pSTAT3.

Figure 1. Signaling pathways involved in EGFR-mediated immunoescape. Interferon γ (IFNγ) promotes the phosphorylation of signal transducer and activator of transcription 1 (STAT1), favoring the upregulation of multiple components of the MHC class I antigen-processing machinery and hence antigen presentation. Conversely, the activation of protein tyrosine phosphatase, non-receptor type 11 (PTPN11, best known as SHP2) by epidermal growth factor receptor (EGFR) results in STAT1 dephosphorylation as well as in the activation mitogen-activated protein kinase (MAPK) signaling, ultimately inhibiting MHC class I-restricted antigen presentation. Similar to the interleukin-6 receptor (IL-6R), EGFR also promotes STAT3 phosphorylation, stimulating the secretion of immunosuppressive cytokines, such as interleukin-10 (IL-10), transforming growth factor β1 (TGFβ1) and vascular endothelial growth factor (VEGF).