Expression of immune checkpoint molecules TIGIT and TIM-3 by tumor-infiltrating lymphocytes predicts poor outcome in sinonasal mucosal melanoma.

ABSTRACT

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is a rare but aggressive tumor with a poor prognosis. The co-inhibitory receptors T cell immunoglobulin and mucinodomain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) are promising new targets in anti-cancer immunotherapy. The expression profiles of these immune checkpoint molecules (ICMs) and potential prognostic implications have not been characterized in SNMM yet. METHODS: Immunohistochemical staining for TIGIT, LAG-3 and TIM-3 was performed on tumor tissue samples from 27 patients with primary SNMM. Associations between ICM expression and demographic parameters, AJCC tumor stage, overall survival, and recurrence-free survival were retrospectively analyzed. RESULTS: SNMM patients with low numbers of TIGIT+ and TIM-3+ tumor infiltrating lymphocytes (TILs) in the primary tumor survived significantly longer than patients with a high degree of TIGIT+ and TIM-3+ TILs. High infiltration with TIM-3+ or TIGIT+ lymphocytes was associated with the higher T4 stage and decreased 5-year survival. CONCLUSION: We identified high densities of TIM-3+ and TIGIT+ TILs as strong negative prognostic biomarkers in SNMM. This suggests that TIM-3 and TIGIT contribute to immunosuppression in SNMM and provides a rationale for novel treatment strategies based on this next generation of immune checkpoint inhibitors. Prospective studies with larger case numbers are warranted to confirm our findings and their implications for immunotherapy.