Expression of C5aR1 in Cutaneous Squamous Cell Carcinoma is Associated with Invasion, Metastasis and Poor Prognosis

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and the metastatic disease is associated with poor prognosis. We have examined the role of complement C5a receptor, C5aR1, in the progression and metastasis of cSCC. C5aR1 expression was increased in cSCC cells in 3D spheroid co-culture model in the presence of fibroblasts, and that treatment with recombinant C5a enhanced the invasion of cSCC cells. Staining for C5aR1 was detected on the surface of tumor cells at the invasive edge of human cSCC xenografts in vivo. Staining of metastatic and non-metastatic primary human cSCCs, premalignant and benign epidermal lesions and normal skin for C5aR1 with multiplex immunofluorescence and chromogenic immunohistochemistry revealed increased expression of C5aR1 on the surface of tumor cells and fibroblasts in invasive cSCCs and recessive dystrophic epidermolysis bullosa-associated cSCCs compared to cSCC in situ, actinic keratoses, seborrheic keratoses and normal skin. Increased expression of C5aR1 on the tumor cell surface and in fibroblasts was associated with metastatic risk and poor disease-specific survival of patients with primary cSCC. These findings reveal the role of C5aR1 in cSCC invasion and identify C5aR1 as a novel biomarker for metastasis risk and poor prognosis in patients with cSCC. The results also suggest that C5aR1 could be a novel therapeutic target for treatment of locally advanced and metastatic cSCC.