159P - Exploring programmed death cell-1 (PD-1) single nucleotide polymorphisms (SNP) as predictive biomarkers for immune-related adverse events (irAEs) in advanced cancer patients treated with immune checkpoint inhibitors (ICIs)

Background

ICIs targeting PD-1 and its ligand 1 (PD-L1) revolutionized the management of many types of tumors. However, a portion of treated patients develops severe irAEs potentially causing prolonged sequelae. As a result, there is the need for biomarkers to identify which patients have a higher likelihood of developing irAEs.

Methods

We assessed the role of PD-1 SNPs as biomarkers for predicting the occurrence of irAEs in advanced cancer patients treated with ICIs. Selected PD-1 SNPs were genotyped by RT-PCR. To assess the mechanism underlying the predictive role of the identified PD-1 SNP, we employed peripheral blood mononuclear cells (PBMCs) isolated from two cancer patients, transfected with specific miRNAs and co-cultured with HaCat cells.

Results

Seventy-two patients including non-small cell lung cancer (49), renal cell carcinoma (9), head and neck squamous cell carcinoma (8) and melanoma (6) were treated with anti-PD-1/PD-L1 therapy. Grade 1-2 and grade 3-4 irAEs were reported in 45 (69.23%) and 6 (9.23%) of the treated patients, respectively. Among selected PD-1 SNPs, rs10204525 exhibited a significant association with grade 1-2 (P < 0.005) and grade 3-4 irAEs (P < 0.002). Indeed, patients carrying allele C reported a higher rate of irAEs than those carrying allele T. rs10204525 mapped on the 3'-UTR region of the PD-1 affecting the binding affinity of specific miRNAs. Specifically, miR-4717 strongly bound to rs10204525 in presence of allele C but not in presence of allele T. The differential binding of miR-4717 to rs10204525, in turn differentially modulated the expression of PD-1 on PMBCs both under basal conditions and following treatment with IFN-ɣ. Moreover, a decreased cell viability, an increased IFN-ɣ release and induction of apoptosis of HaCat cells when co-cultured with miR-4717-transfected PBMCs^C/C were reported. In contrast, no significant difference when HaCat cells were co-cultured with PBMCs^C/T was found.

Conclusions

Our findings have high clinical relevance since identify rs10204525 as an efficient biomarker for predicting the occurrence of irAEs in advanced cancer patients treated with ICIs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Salerno.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.