Molecular and immune landscape of recurrent and/or distant metastatic squamous cell carcinoma of the head and neck: an EORTC/IMMUCAN project.

Abstract

Recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a heterogenous clinical entity with poor prognosis. The molecular and immune landscape of R/M SCCHN is underexplored. To offer a comprehensive view of the tumor microenvironment and molecular profile of R/M SCCHN, we performed an in-depth molecular and immune characterization, evaluating the impact of HPV status, tobacco and alcohol history, primary tumor site, relapse pattern, and treatment history, at the genomic, transcriptomic and immune levels. We analyzed 253 R/M SCCHN fresh tumor biopsies from the IMMUcan project using RNAseq, whole-exome sequencing, and multiplex immunofluorescence (mIF). The primary clinical factor impacting the immune microenvironment was the number of treatment lines, with significant declines in T cells and B cells observed via mIF and RNAseq as the number of R/M treatment lines progressed. IL-6, IL-13, IL-15, and NRF2 pathways were enriched in HPV-negative R/M SCCHN compared to HPV-positive tumors, while no immune differences were detected between these two clinical groups. Specific genomic alterations were observed in laryngeal cancer (DDR2, FOXP1, KLF5, ROBO2), while non-smokers/non-drinkers exhibited alterations in SPEN, PBRM1, and CYLD. 11q13.3 amplification was linked to HPV-negative metastatic tumors and hypopharyngeal cancer. HPV-negative SCCHN with locoregional recurrence showed elevated EGFR and CXCL12 pathway activity. p-EMT transcriptomic signatures correlated with poor survival, while lymphocyte infiltration, especially in the context of TLS, was associated with improved survival. Our study highlights key molecular and immune differences across R/M SCCHN subgroups, identifies potential biomarkers, and suggests biological rationales for tailored therapeutic strategies.