Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy

SIMPLE SUMMARY: Although the introduction of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) has significantly improved the overall survival (OS) in patients with metastatic melanoma, a substantial number of patients do not benefit from ICIs. Therefore, the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis was investigated in patients with metastatic melanoma and anti-PD-1 monotherapy. Germline variation in the gene encoding for PD-1, PDCD1 804C > T (rs2227981), was associated with poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients. In addition, PDCD1 804C > T carriers had significantly lower mRNA expression in several tissues and a decreased fraction of PD-1(+) CD4(+) T cells, indicating that PDCD1 804C > T may affect clinical benefit from ICIs by decreasing transcriptional initiation and PD-1 expression in T cells. These findings show that germline genetics may significantly impact immune responses after ICIs. ABSTRACT: A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were treated with pembrolizumab or nivolumab monotherapy, blood samples were genotyped for 11 SNPs in nine genes. Associations between SNPs and OS were tested using Cox regression analysis and internally validated by bootstrapping. For SNPs with a statistical significance, an expression quantitative trait loci (eQTL) analysis was performed. In a subset of patients, immunophenotyping was performed. Patients with a SNP in PDCD1 (804C > T; rs2227981) had a significantly poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients (hazard ratio [HR] 2.37; 95% CI: 1.11–5.04; p = 0.026). eQTL analysis showed that this SNP was associated with decreased gene expression. In addition, PDCD1 804C > T carriers had a reduced fraction of peripheral PD-1(+)CD4(+) T cells. No other associations between SNPs and OS were found. PDCD1 804C > T is associated with poorer OS after anti-PD-1 monotherapy in patients with metastatic melanoma. This SNP may affect clinical benefit from ICIs by decreasing transcription initiation and expression of PD-1 in T cells.