Oncogenic growth factor signaling mediating tumor escape from cellular immunity

Abstract

Unrestrained growth factor signals can promote carcinogenesis, as well as other hallmarks of cancer such as immune evasion. Our understanding of the function and complex regulation of HER family of receptors has led to the development of targeted therapeutic agents that suppress tumor growth. However, these receptors also mediate escape from recognition by the host immune system. We discuss how HER family of oncogenic receptors downregulate tumor antigen presentation and upregulate suppressive membrane-bound or soluble secreted inhibitory molecules that ultimately lead to impaired cellular immunity mediated by cytotoxic T lymphocyte (CTL) recognition. Implementing this knowledge into new therapeutic strategies to enhance tumor immunogenicity may restore effector cell mediated immune clearance of tumors and clinical efficacy of tumor-targeted immunotherapy against HER receptor overexpression.

Figure 1. EGFR/HER2 mediated immunoescape

EGFR stimulation induces activation of phosphatase SHP2 which decreases phosphorylation of STAT1 and subsequently expression of HLA class I and APM components. Conversely, EGFR mediated activation of JAK2-STAT1 induces expression of PD-L1. Likewise, mutant EGFR/RAS-MAPK pathway induces expression of PD-L1 as reported in NCSLC. Other pathways involved in PD-L1 expression are depicted on the left, PI3K and NPM/ALK-STAT3 pathways have been reported to upregulate PD-L1 in glioblastoma and T cell Lymphoma, respectively. EGFR/HER2 stimulation induces secretion of IL-8, IL-6, CCL2, CCL3, CCL5, eotaxin, GM-CSF inducing chronic inflammation and escape from T cell recognition. Overall, EGFR mediated downregulation of signal 1 and upregulation of suppressive signals 2 and 3, favoring escape from CTL recognition.