%0 Journal Article
%T A Functional Interaction Between rs10204525 and miR-4717-3p Regulates PD-1 Levels and Serves as a Biomarker for Immune-Related Toxicity During Anti-PD-1/PD-L1 Treatment in Advanced Cancer
%A Emily Rose Carter
%A Jonathan Michael Lee
%J Archive of International Journal of Cancer and Allied Science
%@ 3108-4834
%D 2021
%V 1
%N 1
%R 10.51847/aYEtM32NYo
%P 85-102
%X Despite widespread clinical use of antibodies targeting programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1), dependable biomarkers for anticipating immune-related adverse events (irAEs) remain largely unavailable. This investigation examined whether inherited variation within the PD-1 gene could identify patients at increased risk of irAEs following immune checkpoint blockade and clarified the molecular mechanism through which the most relevant variant exerts its biological effects. Clinical data, toxicity profiles, survival outcomes, and peripheral blood samples were obtained from two independent populations: one comprising patients with advanced malignancies receiving anti–PD-1/PD-L1 monotherapy, and a second including patients with advanced non-small cell lung cancer (NSCLC) treated with anti–PD-1 combined with platinum-based chemotherapy, with or without anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4). Six PD-1 single nucleotide polymorphisms (rs2227981, rs7421861, rs11568821, rs36084323, rs2227982, and rs10204525) were genotyped and analyzed for associations with clinicopathological features and irAE incidence. Bioinformatic screening was used to identify microRNAs predicted to interact with the candidate SNP. Allele-dependent miRNA binding and its regulatory impact on PD-1 expression were experimentally assessed in patient-derived peripheral blood mononuclear cells (PBMCs). Functional immune reactivity was examined using co-culture systems in which HLA-matched PBMCs from genotyped patients were incubated with non-malignant human epidermal keratinocytes (HaCaT) or bronchial epithelial cells (BEAS-2B) in the presence of immune checkpoint inhibitors.

No significant association with irAE development was observed for most PD-1 polymorphisms evaluated. In contrast, rs10204525 showed a consistent and statistically significant correlation with both low-grade (1–2) and high-grade (3–4) irAEs in both cohorts. Patients homozygous for the C allele experienced irAEs more frequently than heterozygous carriers. This polymorphism was located within the 3′ untranslated region (3′-UTR) of PD-1 and demonstrated allele-specific interaction with miR-4717-3p. Manipulation of miR-4717-3p levels and disruption of its binding to rs10204525 produced genotype-dependent differences in PD-1 expression and inducibility in PBMCs. These molecular alterations translated into functional consequences, as PBMCs carrying the C/T genotype exhibited diminished capacity to recognize and eliminate HLA-matched non-cancer cells compared with C/C PBMCs, an effect that was accentuated following anti–PD-1 exposure. Independent validation experiments using additional patient-derived PBMCs and combined anti–PD-1/anti–CTLA-4 treatment confirmed these findings across both HaCaT and BEAS-2B co-culture models. This study identifies an rs10204525–miR-4717-3p regulatory axis that governs PD-1 expression and shapes immune cell responsiveness toward non-malignant tissues, establishing rs10204525 as a clinically relevant biomarker for predicting irAEs in patients undergoing anti–PD-1/PD-L1-based immunotherapy.
%U https://smerpub.com/article/a-functional-interaction-between-rs10204525-and-mir-4717-3p-regulates-pd-1-levels-and-serves-as-a-bi-kcb3c0pjwcr06gm