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High-dimensional and spatial analysis reveals immune landscape dependent progression in cutaneous squamous cell carcinoma

Purpose The tumour immune microenvironment impacts the biological behaviour of the tumour but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. Experimental Design We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasised using multi-parameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumour behaviour. Results Non-progressing primary HNcSCC were characterised by higher CD8+ and CD4+ T cell responses, including numerically increased Regulatory T cells. By contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterised by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with non-progressing primary tumours that were distinct in primary tumours of disease progressing patients. Cellular regional analysis of the tumour microenvironment also shows squamous cell-enriched tumour regions associated with primary non-progressing tumours. Conclusions Effective responses from both CD8+ and CD4+ T cells in the tumour microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumours dictate progression and disease outcomes in HNcSCC. Translational Relevance The ability to predict metastatic tumour progression at the time of initial diagnosis of primary HNcSCC could tailor personalised medical care including disease surveillance strategies and identifying patients who will benefit most from adjuvant therapy. One Sentence Summary The immune landscape of high-risk cutaneous squamous cell carcinoma differs in tumours that never progress compared to those that progress to metastasis.