The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors

A Boutros; R Carosio; D Campanella; F Spagnolo; B Banelli; A Morabito; M P Pistillo; E Croce; F Cecchi; P Pronzato; P Queirolo; E Raposio; V Fontana; E T Tanda

doi:10.1016/j.iotech.2023.100408

The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors

Immunooncol Technol. 2023 Sep 29:20:100408. doi: 10.1016/j.iotech.2023.100408. eCollection 2023 Dec.

Authors

A Boutros^{1

2}, R Carosio³, D Campanella⁴, F Spagnolo^{1

5}, B Banelli³, A Morabito³, M P Pistillo³, E Croce^{1

2}, F Cecchi¹, P Pronzato¹, P Queirolo⁶, E Raposio⁵, V Fontana⁴, E T Tanda¹

Affiliations

¹ Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa.
² Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa.
³ Tumor Epigenetics Unit, IRCCS Ospedale Policlinico San Martino, Genoa.
⁴ Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa.
⁵ Department of Surgical Sciences and Integrated Diagnostics (DISC), Plastic Surgery Division, University of Genova, Genoa.
⁶ Division of Melanoma Sarcoma and Rare Tumors, IRCCS European Institute of Oncology, Milan, Italy.

Abstract

Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis.

Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS.

Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model.

Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.

Keywords: PD-1; PD-L1; SNV; melanoma; single nucleotide gene variant.