Implication of IL6-positive Cancer-associated Fibroblasts in Merkel Cell Carcinoma Pathogenesis: A Possible Modulator of Immune Microenvironment

Background/Aim: The role of cancer-associated fibroblasts (CAFs) in the pathogenesis of Merkel cell carcinoma (MCC) remains unknown. This study aimed to investigate the clinicopathological significance of CAF subpopulations and their association with tumor-infiltrating lymphocytes (TILs) in patients with MCC. Materials and Methods: Clinicopathological features and the status of microenvironment fibrosis (MF) around tumor masses were evaluated in 20 MCC patient and tissue sections. Alpha-smooth muscle actin (α-SMA)-positive CAFs (α-SMA⁺CAFs), interleukin-6-positive CAFs (IL6⁺CAFs), CD4-positive TILs (CD4⁺TILs), and CD8-positive TILs (CD8⁺TILs) in MCC tissue samples were investigated using immunohistochemistry. Results: In a total of 20 MCC patients, high-MF was detected in 12 (60%) patients which was significantly associated with worse progression-free survival (p=0.048), but not with overall survival. CD4⁺/CD8⁺ TILs were frequently detected in MCC tissues. High-intra-tumoral CD8⁺TIL was significantly associated with better overall and progression-free survival (p=0.04 and p=0.015) in our cohort. High-αSMA⁺ CAFs were detected in 11 (55.0%) patients and high-IL6⁺CAFs in 10 (50.0%) patients. A negative association was found between high-IL6⁺CAF and high-intra-tumoral CD8⁺TILs (p=0.005). Patients with high IL6⁺CAFs showed worse overall/progression-free survival than patients with lowIL6⁺CAFs (p=0.022 and p=0.035). Conclusion: IL6⁺CAFs may largely influence the tumor immune microenvironment of MCC by modulating distinct T-cell populations and functions. This study provides a possible therapeutic target to overcome resistance to immune therapies in MCC.