Nuclear EGFR Block Expression of MHC Class-I Related Genes Necessary for Natural Killer Cell Recruitment and Cytotoxicity

Abstract

Nuclear Epidermal Growth Factor Receptor (nEGFR) driven triple negative breast cancer (TNBC) can exhibit therapeutic resistance and immune evasion in vivo, making treatment difficult. Nuclear EGFR may be promoting immune evasion by suppressing Natural Killer (NK) activating-ligands within the tumor. Here, we show that the novel drug, cSNX1.3, blocks retrograde trafficking of EGFR to the nucleus, allowing the MHC Class I-Related genes RAET1H (ULBP2), RAET1G (ULBP5), and RAET1L (ULBP6) to be expressed. We also demonstrate that cSNX1.3 blocks wound-healing migration in both immortalized epithelial MCF-10A cells and MDA-MB-468 TNBC cells, and that the MHC Class I and Class-I Related genes of interest are present in both cell lines, but only upregulated with cSNX1.3 treatment in the MDA-MB-468 TNBC cell line. We show that siRNA can be used to transiently knock down RAET1H/G/L (ULBP2/5/6) at once, and we use this siRNA to suggest that ULBP2/5/6 expression may increase NK-92 recruitment and NK-92-mediated cytotoxicity. Overall, this work further characterizes the role of nEGFR in driving oncogenic migration and suggests both a mechanism and a solution for nEGFR-driven immune evasion in vivo with cSNX1.3 peptide drug.