Current and emerging insights into the causes, immunopathogenesis, and treatment of cutaneous squamous cell carcinoma

Abstract

The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a brief overview of the well-recognized epidemiology, clinical features, and diagnosis of cSCC, the current review is focused on risk factors, most prominently excessive exposure to ultraviolet radiation (UVR) as a cause of persistent, pro-tumorigenic mutagenesis, and immune suppression. The next phase of the review encompasses an evaluation of the search for key driver mutations in the pathogenesis of cSCC, including the role of these and other mutations in the formation of immunologically reactive neoepitopes. With respect to additional mechanisms of tumorigenesis, immune evasion is prioritized, specifically the involvement of cell-free and infiltrating cellular mediators of immune suppression. Prominent amongst the former are the cytokine, transforming growth factor-β1 (TGF-β1), the prostanoid, prostaglandin E2, and the emerging immune suppressive nucleoside adenosine. In the case of the latter, tumor-infiltrating and circulating regulatory T cells have been implicated as being key players. The final sections of the review are focused on an update of the immunotherapy of established and advanced disease, as well as on the search for novel, reliable lesional and systemic biomarkers with the potential to guide patient management.SIMPLE SUMMARY : The incidence of cutaneous squamous cell carcinoma is increasing worldwide coincident with global warming. The high mutational burden and associated immunosuppression are the most prominent triggers. Once established, persistence of the tumor is achieved via localized and systemic mechanisms of immune evasion. Prominent mediators of immune evasion include transforming growth factor-β1 (TGF-β1), prostaglandin E2 (PGE2) and regulatory T cells. Circulating tumor DNA represents a promising systemic biomarker of disease progression. Combined targeting of TGF-β1, PGE2 and PD-1 shows considerable therapeutic promise.