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

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.

Severe Immune-Related Adverse Events in Patients Treated with Nivolumab for Metastatic Renal Cell Carcinoma Are Associated with PDCD1 Polymorphism

“…In patients with the PD-1.6 GG genotype, miRNA-4717 mimics a significantly decreased PD-1 expression [ 21 ]. In general, a high PD-1 expression seems to be related to a substantial antitumor effect and the development of irAEs induced by nivolumab administration [ 15 ]. However, the quantity of PD-1 protein is reduced in children with new-onset autoimmune diseases and type I diabetes compared with those negative for auto-antibody (AAB) presence [ 34 ].…”

“…There are several approaches to identify clinically useful genetic variations. For instance, single nucleotide polymorphisms (SNPs) reportedly influence the effect of nivolumab [ 15 ]. A SNP is a genomic variant at a single base position in the DNA and may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may affect the development of disease.…”

Challenges of the Immunotherapy: Perspectives and Limitations of the Immune Checkpoint Inhibitor Treatment

“…Not surprisingly, several germline mutations have been also connected with the cancer response to immunotherapy, especially inside genes involved in DNA repair mechanisms or checkpoint proteins, but also the INFγ signalling pathway, antigen presentation mechanisms and immune response itself [ 69 ]. For example, it has been shown that overall survival of patients with the germline variant of the gene PDCD1 804C>T (rs2227981) decreased significantly: for the wild-type variant the three-year survival rate was 71%, whereas for the mutant variant the three-year survival rate was 51.8% [ 6 , 70 ]. In fact, this single nucleotide genetic variant affected the clinical efficacy of immune checkpoint inhibitors, reducing the initiation of the transcription, as well as the expression of the PD-1 protein on the T cell surface [ 70 ].…”

“…For example, it has been shown that overall survival of patients with the germline variant of the gene PDCD1 804C>T (rs2227981) decreased significantly: for the wild-type variant the three-year survival rate was 71%, whereas for the mutant variant the three-year survival rate was 51.8% [ 6 , 70 ]. In fact, this single nucleotide genetic variant affected the clinical efficacy of immune checkpoint inhibitors, reducing the initiation of the transcription, as well as the expression of the PD-1 protein on the T cell surface [ 70 ]. A different single nucleotide variant, ALDH2 rs671, playing a key role in the detoxification of endogenous acetaldehyde, resulted in decreased enzyme activity [ 71 ].…”

Recent advances in primary resistance mechanisms against immune checkpoint inhibitors

“…It has been reported that the OS of patients with the germline variant PDCD1 804C>T (rs2227981) deteriorated significantly, and the 3-year survival rate was 51.8%, whereas that of wild-type patients was 71.0% (OR 2.366; 95% CI 1.111–5.036; P = 0.026). Initial studies on mechanism have shown that this single nucleotide polymorphism may affect the clinical efficacy of ICIs by reducing the transcription initiation and expression of PD-1 in T cells [ 75 ]. Compared with A/G genotype, patients with PD1.3 (rs11568821) G/G genotype have a higher complete response (16.5% vs. 2.6%) [ 76 ].…”