Comprehensive profiling identifies tumour and immune-microenvironmental differences in clinical subsets of cutaneous squamous cell carcinoma.

Abstract

Cutaneous squamous cell carcinomas (CSCC) are the second most diagnosed skin cancer worldwide, however, little is known about the pathobiological factors contributing to the diverse clinical outcomes observed. To comprehensively profile CSCC and identify pathological processes contributing to the disparities in clinical behaviour observed. We characterised the genomic, transcriptomic and immunohistochemical profiles of 206 CSCC tumours, including 37 CSCC from immunocompromised patients. CSCC from immunocompromised patients are characterised by the lack of B cells in the peri-tumoural stromal compared to immunocompetent patients. Further, the abundance of a memory B cell-like population in the peritumoural stroma is associated with better prognosis in all patients (immunocompetent and immunocompromised) as well as only immunocompetent patients. No differences in genetic variants, tumour mutational burden or mutational signatures were observed between CSCC from immunocompetent and immunocompromised patients. Thus, differences in survival between CSCC from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but rather associated with differential host immune response. Non-head and neck primary site CSCC have lower tumour mutational burden and exhibit upregulation of the epithelial-mesenchymal transition programme compared to head and neck CSCC. Both factors are implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. In summary, we identify tumour and host immune factors that contribute to the disparate clinical behaviour of CSCC with broad translational application including prognostication, treatment prediction to current therapies and identifying novel anti-cancer therapy approaches in CSCC.