High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations

• DOI: 10.1080/2162402x.2017.1284719
• Publication Date: 2017-01-31T08:50:49Z
• Authors: Amélie Boichard; Igor F. Tsigelny; Razelle Kurzrock
• Keywords: APOBEC; Microsatellite Instability; Immune checkpoint

Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates ligand (PD-L1 or PD-L2) expression, positivity represents only a part of predictive model necessary for selecting predisposed respond immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related 8,475 pan-cancer samples available The Cancer Genome Atlas (TCGA) conducted logistic regression analysis based on large set variables, microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) ϵ (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) lymphocyte markers mutation burden estimates determine independent factors that associate overexpression. overexpression was independently significantly correlated mutations APOBEC3 paralogs. Additionally, while high tumor PD-L1 have been previously each other, we demonstrate specific pattern caused by APOBEC enzymes called kataegis—rather than overall burden, MSI-H MMR alterations—correlates PD-L1/PD-L2 expression. These observations suggest kataegis play an important role regulation overexpression, thus, their relationship immune inhibitor warrants exploration.