Genomic and Immune Landscape of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Progressing on Anti–PD-1 Treatment

Anti-PD-1 therapies improve survival in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), but only a minority of patients achieve durable responses. The mechanisms driving resistance to anti-PD-1 in SCCHN remain poorly understood. Using the IMMUcan multiomics workflow, we characterized the molecular and immune profiles of R/M SCCHN progressing on anti-PD-1 treatment and compared them with an anti-PD-1-naïve cohort. Tumor biopsies from patients with anti-PD-1-resistant SCCHN exhibited significantly more EGFR and MYCL amplifications, along with increased MYC pathway alterations. Transcriptomic and proteomic analyses revealed that anti-PD-1-secondary resistant SCCHN had increased CD8+ T-cell infiltration with higher levels of immune exhaustion markers than primary resistant and naïve SCCHN. Additionally, high beta-2-microglobulin (B2M) expression correlated with greater T-cell infiltration and improved survival following anti-PD-1 therapy. Tumor cell B2M expression was independent of TMB and PD-1L expression, suggesting that B2M expression could serve as an additional biomarker for anti-PD-1 response.