Year: 2024
Type: article
Abstract: 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 (EGFRΔNLS) 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.
Source: Oncogene
Authors: Angelica Escoto, Ryan Hecksel, Chance Parkinson, Sara Crane, Benjamin Atwell, Shyanne King, Daniela Ortiz Chavez, Alison Jannuzi, Barbara Sands, Benjamin G. Bitler, Todd A. Fehniger, Andrew L. Paek, Megha Padi, Joyce Schroeder
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,690
Awards: Graduate Training in Biochemistry and Molecular Biology, G2277093813, G2802122546, Dynamics of the FOXO transcription factor network, G4534458934, G4950047026, G7934591450, MARC Biomedical Research and Training Program at the University of Arizona, G9000066947, Targeting Wnt signaling in therapy-resistant ovarian cancer, University of Arizona's Initiative for Maximizing Student Development (IMSD), Graduate Training in Biochemistry and Molecular Biology, Specialized Program of Research Excellence (SPORE) in Leukemia, Cancer Center Support Grant, University of Arizona Cancer Center - Cancer Center Support Grant, Unraveling the regulatory circuits that drive Merkel cell carcinoma, G903185969
OpenAlex ID: W4404199955