HER3 and HPV in head and neck squamous cell carcinoma: Potential implications of induction chemotherapy on tumor immune microenvironment

Receptor tyrosine-protein kinase erbB-3 (HER3) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and is typically associated with chemotherapy resistance and poor prognosis. However, the dynamics of HER3 expression following induction chemotherapy (ICT) remain poorly understood, and its impact on the tumor immune microenvironment (TIME) is largely unknown. We analyzed 98 patients with locally advanced HNSCC who received ICT between 2012 and 2020. HER3 immunohistochemistry (IHC) was performed using the D22C5 clone on formalin-fixed paraffin-embedded specimens collected pre- and/or post-ICT. HPV status was determined for all samples. Compositional changes in immune cell subsets within the tumor and peritumoral areas were evaluated via multiplex IHC. The cohort (mean age: 62.9 years; 83.3% male) predominantly presented with stage III or IV disease (97.2%). The oropharynx was the most common primary site (66.7%), with 52.8% of patients being HPV-positive. High HER3 expression (H-score >100) strongly correlated with HPV positivity (p=0.005), particularly within oropharyngeal tumors (p=0.003). The objective response rate (ORR) to ICT was higher in the HER3-high group compared to the HER3-low group (87% vs. 69%; p=0.090), a trend consistent with HPV status (p=0.090). In 16 paired samples, HER3 expression increased post-ICT, most notably among smokers. Patients with high HER3 expression tended to have longer relapse-free survival and improved overall survival (76.3 vs. 42.4 months; p = 0.168) compared to those with low HER3 expression. At baseline, the tumor immune microenvironment (TIME) of HER3-high tumors was significantly enriched with CD4 + FoxP3 + regulatory T cells (Tregs), compared to HER3-low tumors (p=0.032). Post-ICT, HER3-high tumors exhibited a marked depletion of Tregs (p=0.019), while CD8 + cytotoxic T cells increased significantly across all groups (p<0.01). Finally, external validation using TCGA-HNSCC database confirmed that HER3 mRNA expression is positively associated with Tregs enrichment, independent of HPV status. High HER3 expression in HNSCC is significantly associated with HPV positivity and predicts favorable clinical outcomes following ICT. Our findings suggest that ICT modulates the TIME by depleting immunosuppressive CD4 + FoxP3 + Tregs specifically in HER3-high tumors while simultaneously recruiting immunostimulatory CD8 + T cells regardless of HER3 expression. This shift potentially converts an immunosuppressive environment into an immunostimulatory one. • High HER3 expression is strongly associated with HPV positivity in HNSCC. • HER3-high tumors show a Treg-enriched immune microenvironment at baseline. • Induction chemotherapy selectively reduces Tregs in HER3-high tumors