Nuclear EGFR in breast cancer suppresses NK cell recruitment and cytotoxicity

Natural Killer (NK) cells can target and destroy cancer cells, yet tumor microenvironments typically suppress NK cell recruitment and cytotoxicity. The epidermal growth factor receptor (EGFR) is a potent oncogene that can activate survival, migration, and proliferation pathways, and clinical data suggests it may also play an immunomodulating role in cancers. Recent work has demonstrated a novel role for nuclear EGFR (nEGFR) in regulating transcriptional events unique from the kinase domain. Using a novel peptide therapeutic (cSNX1.3) that inhibits retrograde trafficking of EGFR and an EGFR nuclear localization mutant, we discovered that nEGFR suppresses NK cell recruitment and cytotoxicity. RNA-Seq analysis of breast cancer cells treated with cSNX1.3 or modified to lack a nuclear localization sequence (EGFR^ΔNLS) revealed the EGF-dependent induction of NK activating receptor ligands, while kinase inhibition by erlotinib did not impact these genes. NanoString analysis of tumor-bearing WAP-TGFα transgenic mice treated with cSNX1.3 demonstrated an increase in immune cell populations and activating genes. Additionally, immunohistochemistry confirmed an increase in NK cells upon cSNX1.3 treatment. Finally, cSNX1.3 treatment was found to enhance NK cell recruitment and cytotoxicity in vitro. Together, the data demonstrate a unique immunomodulatory role for nEGFR.