Description
EGFR Activation Contributes to Immune Evasion in HNSCC
Sean Korpela1, Trista Hinz2, Raphael Nemenoff3, Sana Karam4, Ayman Oweida4, Lynn Heasley1,2
Departments of 1Pharmacology, 2Craniofacial Biology, 3Medicine, and 4Radiology -
University of Colorado Denver
Epidermal growth factor receptor (EGFR) is highly overexpressed in head and neck squamous cell carcinomas (HNSCC), and EGFR inhibitors, when used as single agents or in combination with chemotherapy or radiotherapy, have modestly improved overall survival. Recent clinical trials targeting the immune checkpoint programmed-death ligand axis (PD-1/PD-L1) have shown profound responses in some HNSCC patients, yet most (~85%) patients are resistant to PD-1/PD-L1 inhibition. The insensitivity to immune checkpoint blockade has been proposed to be due to lack of tumor cell inflammation and T-cell infiltration. Transcriptional profiling of human HNSCC cell lines treated for 3 days with the EGFR-specific TKI, gefitinib, revealed marked reprogramming of the interferon (IFN) alpha pathway, the most significantly enriched as identified by GSEA. Multiple IFN-stimulated genes (ISGs) including STAT1, classic antiviral genes (IFIT1, MX2) and T cell recruiting chemokines (CXCL10) were identified and also confirmed in a murine EGFR-dependent HNSCC cell line, B4B8, in response to cetuximab and a pan-ERBB inhibitor, AZD8931. Since many of the ISGs are predicted to lead to immune cell infiltration, we explored whether inhibition of the EGFR pathway with cetuximab could be utilized to manipulate the inflammatory state of murine B4B8 HNSCC tumors orthotopically-propagated in immune competent BALB/c hosts to enhance sensitivity to immune checkpoint therapy. While the B4B8 tumors were resistant to cetuximab or anti-PD-L1 monotherapy, the combination of cetuximab and PD-L1 blockade induced significant tumor regression and improved survival. This effect was associated with a 4-fold increase in intratumoral CD3 staining, suggesting that cetuximab treatment resulted in augmented T-cell infiltration. These findings provide evidence that signaling events, such as oncogenic EGFR, directly contribute to immune evasion mechanisms. Furthermore, our findings suggest that manipulation of the EGFR pathway can be a means to induce sensitivity to anti-PD1/PD-L1 therapies and thus serve as an applicable combination treatment regimen for HNSCC patients with poorly immunogenic tumors.
Funding:
2017 Colorado CCTSI TL1 Awardee