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-SMACAFs), interleukin-6-positive CAFs (IL6CAFs), CD4-positive TILs (CD4TILs), and CD8-positive TILs (CD8TILs) 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 CD8TIL 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-IL6CAFs in 10 (50.0%) patients. A negative association was found between high-IL6CAF and high-intra-tumoral CD8TILs (p=0.005). Patients with high IL6CAFs showed worse overall/progression-free survival than patients with low-IL6CAFs (p=0.022 and p=0.035).

CONCLUSION

IL6CAFs 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.