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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. [ABSTRACT FROM AUTHOR]