Abstract
Abundance and signaling of the epidermal growth factor receptor (EGFR) and programmed cell death protein ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC) are not only genetically determined but are also subject to the traits of the tumor microenvironment, which has hitherto not been clarified completely. We investigated the impact of hypoxia on the EGFR system and on PD-L1 in six HPV negative HNSCC cell lines in vitro and in FaDu xenografts in vivo. Protein levels of EGFR, AKT, pAKT, ERK1/2, pERK1/2, CA IX, cleaved PARP (apoptosis), LC3B (autophagy), and PD-L1 were quantified by western blot after oxygen deprivation or CoCl2, staurosporine, and erlotinib treatment. In FaDu xenograft tumors the expression of EGFR, CA IX andCD34 staining were analyzed. Reduced oxygen supply strongly downregulated EGFR protein levels and signaling in FaDu cells in vitro and in vivo, and a transient downregulation of EGFR signaling was found in three other HNSCC cell lines. PD-L1 was affected by oxygen deprivation in only one HNSCC cell line showing increased protein amounts. The results of this study indicate a significant impact of the traits of the tumor microenvironment on crucial molecular targets of cancer therapies with high clinical relevance for therapy resistance and response in HNSCC.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) of the oral cavity, oropharynx, hypopharynx, or larynx are the sixth most common cancers worldwide accounting for more than 550,000 new cases and 380,000 deaths per year with a predicted increase [1]
We have demonstrated that the expression of epidermal growth factor receptor (EGFR) is downregulated in diffusion-limited, hypoxic areas of the tumor microenvironment of HNSCCs [24]
The overall cell cycle distribution was comparable between all HNSCC cell lines (Figure 1B)
Summary
Head and neck squamous cell carcinomas (HNSCCs) of the oral cavity, oropharynx, hypopharynx, or larynx are the sixth most common cancers worldwide accounting for more than 550,000 new cases and 380,000 deaths per year with a predicted increase [1]. Immune checkpoint inhibitor therapies showed durable improvements in outcomes of HNSCC patients, but as for EGFR-targeted therapies, response rates are very low and tumor cells frequently acquire immunosuppressive resistance to the cytotoxic activity of immune effectors [10,11,12,13]. Beyond an inhibition of the EGFR-signaling cascade, anti-EGFR IgG1-antibodies induce antibody-dependent, cell-mediated cytotoxicity (ADCC) in HNSCC and, act as an anti-cancer immunotherapeutic agent itself [14] This offers great potential for a combination of anti-EGFR IgG1-antibodies with immune checkpoint inhibitors in a multimodal setting to amplify the anti-cancer immune response, and to increase response rates and the duration of the response [14, 15]
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