Pathophysiology

With ultra-violet light exposure as the dominant risk factor for cSCC, these tumors harbor high mutational burdens. In the treatment of other malignancies, high mutation burden has been associated with clinical benefit from targeting the immune system with immunotherapy.

The role of adaptive immunity is significant in the tumorigenesis of cSCC given that up to 10% of tumor-infiltrating cells are T-cells. The coordination of specific immune responses to diverse threats, including cancer cells, is possible due to the differentiation of naïve T-cells to distinct, specialized T-cell subpopulations (Figure 1). A review of these key immune agents is helpful in understanding their roles in tumorigenesis.

• CD8+ T-cells (CTL) are capable of tumor cell killing and associated with a good prognosis in a variety of cancers.
• Th1 cells are involved in the control of pathogens in the phagocytic cells and produce the proinflammatory cytokines IFN-𝛾 and IL-2.
• Th2 and Th17 cells constitute two other major T-cell subsets found within the tumor microenvironment. Th2 cells, known to provide help to B-cells and involved in extracellular parasite immunity, produce cytokines such as IL-4, IL-5, and IL-13. In contrast, Th17 cells, which are involved in antimicrobial immunity, produce mainly proinflammatory cytokines including IL-17A, IL-17F, and IL-22. Although these two cell types appear to be pro-tumoral overall, they also display antitumoral responses in some tumors.
• Treg cells, are characterized by the production of major suppressive cytokines, including IL-10 and transforming growth factor-𝛽 (TGF-𝛽). In cancer immunity, the presence of Treg cells in the tumor correlates with a bad prognosis.
• Th9 cells constitute an interesting emerging subset, which is mainly associated with a good outcome in solid tumors including melanoma.

Notably, the immunosuppressive cytokines TGF-𝛽 and IL-10 are overexpressed in high-grade cSCC.