Expression of lymphocyte-activating gene 3 and T-cell immunoreceptor with immunoglobulin and ITIM domains in cutaneous melanoma and their correlation with programmed cell death 1 expression in tumor-infiltrating lymphocytes

Background: Lymphocyte-activating gene 3 (LAG-3) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif (TIGIT) domains are emerging checkpoint proteins. Objective: We evaluated LAG-3 and TIGIT protein expression patterns, correlated these patterns with programmed cell death 1 (PD-1) protein expression, and determined their effects on clinicopathologic characteristics and biologic responses in melanoma. Methods: Diagnostic tissue from 124 patients with melanoma were evaluated for LAG-3, TIGIT, and PD-1 expression by immunohistochemistry. Clinicopathologic features and survival were analyzed according to the expression of LAG-3, TIGIT, and PD-1. Results: LAG-3 and TIGIT expression on tumor-infiltrating lymphocytes were significantly correlated with that of PD-1 and was also significantly associated with negative prognostic factors: deeper Breslow thickness, lymph node involvement, and advanced stage of disease. However, PD-1 expression was not associated with clinicopathologic variables of prognostic significance. High expression of either LAG-3 or TIGIT was associated with worse survival. Subgroup analysis on the basis of Breslow thickness showed that both LAG-3 and TIGIT have prognostic significance regardless of tumor thickness. High expression of PD-1 was not predictive of survival. Limitations: Retrospective study in a single institution and possibility of type 1 error. Conclusion: Expression of LAG-3 and TIGIT represents an independent unfavorable prognostic factor in cutaneous melanoma.