Tumor-Infiltrating Immune Cells and HLA Expression as Potential Biomarkers Predicting Response to PD-1 Inhibitor Therapy in Stage IV Melanoma Patients

Abstract

PD-1 inhibitors are known to be effective in melanoma; however, a considerable proportion of patients fail to respond to therapy, necessitating the identification of predictive markers. We examined the predictive value of tumor cell HLA class I and II expression and immune cell infiltration in melanoma patients treated with PD-1 inhibitors. Pretreatment surgical samples from 40 stage IV melanoma patients were studied immunohistochemically for melanoma cell expression of HLA class I molecules (using four antibody clones with different specificities), HLA-II, and immune cell infiltration (using a panel of 10 markers). Among the responders, the ratio of patients showing melanoma cell HLA-II expression was higher compared to non-responders (p = 0.0158), and similar results were obtained in the case of two anti-HLA-I antibodies. A combined score of HLA-I/II expression also predicted treatment response (p = 0.0019). Intratumoral infiltration was stronger in the responders for most immune cell types. Progression-free survival showed an association with HLA-II expression, the combined HLA score, and the density of immune cells expressing CD134 and PD-1, while overall survival was significantly associated only with HLA class II expression. Our findings corroborate previous results indicating the importance of immune cell infiltration and tumor cell HLA-II expression in the efficacy of PD-1 inhibitor treatment in a “real world” patient cohort and suggest the potential predictive role of HLA class I expression.

Keywords

• melanoma
• immunotherapy
• PD-1 inhibitors
• biomarker
• tumor-infiltrating immune cells
• HLA class I and II expression