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. 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 (EGFRΔNLS) revealed the EGF-dependent induction of NK activating antigens, while kinase inhibition by erlotinib did not impact these genes. Together, the data demonstrate a unique immunomodulatory role for nEGFR.