Chemokine level predicts the therapeutic effect of anti-PD-1 antibody (nivolumab) therapy for malignant melanoma.

ABSTRACT

Anti-programmed cell death protein 1 (PD-1) antibody drugs, nivolumab and pembrolizumab, are regarded as first-line therapies for advanced malignant melanoma. Anti-PD-1 therapy suppresses tumor immunity, and the therapeutic effect is frequently correlated with the number of tumor-infiltrating lymphocytes (TIL) and tumor mutation burden (TMB). However, sampling tumor tissues from the metastatic sites to examine the number of TILs and TMB level is often challenging. Herein, we focused on chemokines in blood to determine whether they can predict the therapeutic effect of anti-PD-1 (nivolumab) therapy. First, we measured 44 types of chemokines and cytokines in the blood of 8 advanced malignant melanomas before anti-PD-1 (nivolumab) treatment and examined the relationship between the levels of these proteins and therapeutic effect of the drug treatment, which suggested that C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine ligand 12 (CXCL12) were candidates for biomarkers to predict the therapeutic effect of anti-PD-1 therapy. Next, we measured the blood levels of CCL5 and CXCL12 in 22 patients with advanced malignant melanomas before the administration of anti-PD-1 antibody. We evaluated tumor infiltration of CD8-positive T cells by immunostaining in nine patients in whom the metastatic site could be sampled at the beginning of the treatment. The patients with lower than average levels of CCL5 and CXCL12 had a large number of TILs (P = 0.04) and good disease-specific survival rate (P = 0.04). Therefore, CCL5 and CXCL12 could likely be used as biomarkers to predict the therapeutic effect of anti-PD-1 (nivolumab) therapy.