A Distinctive Lineage-Negative Cell Population Produces IL-17A in Cutaneous Squamous Cell Carcinoma

Interleukin (IL)-17A is a key proinflammatory cytokine indicated in multiple pathologies, including skin tumorigenesis. While IL-17A is a signature cytokine of Th17 cells, IL-17A is also produced by other cell types, including type 3 innate lymphoid cells (ILC3s) in the skin, particularly in patients with psoriasis. Interestingly, we detect CD45⁺Lin^-(CD3^-CD14^-CD19^-CD20^-) IL-17A⁺ cells in the cutaneous squamous cell carcinomas (cSCCs) by flow cytometry of the cell suspensions prepared from tumor tissues. Consistently, we found CD3^-IL-17⁺ cells in tumor tissue of skin cSCCs by immunohistochemistry staining of serial sections of SCCs from both immunocompetent and immunocompromised patients (e.g., transplant patients on iatrogenic long-term immunosuppressive therapy). In several immunocompromised patients, the CD3^-IL-17⁺ cells consist of over 90% of the total IL-17⁺ cells in the tumor tissue. Furthermore, these CD3^-IL-17⁺ cells are negatively stained for SMA, CD11b, and CD19, suggesting that they are unlikely to be fibroblast, myeloid cells, or B cells. Taken together, we found a population of lineage-negative IL-17A-producing cells present in the cSCCs, which share the "CD45⁺Lin^-" features with ILCs. This study suggests that IL-17A can be produced by immune cell populations other than T cells in skin SCCs.