title: High expression of PD-1 ligands is associated withkataegismutational signature and APOBEC3 alterations.
abstract: Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) and polymerase ε (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression. PD-1 ligand overexpression was independently and significantly correlated with overexpression of and mutations inAPOBEC3paralogs. Additionally, while high tumor mutation burden and overexpression of PD-L1 have been previously correlated with each other, we demonstrate that the specific mutation pattern caused by APOBEC enzymes and calledkataegis-rather than overall mutation burden, MSI-H or MMR alterations-correlates independently with PD-L1/PD-L2 expression. These observations suggest thatAPOBEC3alterations, APOBEC3 overexpression andkataegisplay an important role in the regulation of PD-1 ligand overexpression, and thus, their relationship with immune checkpoint inhibitor response warrants exploration.
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California San Diego, Moores Cancer Center , La Jolla, CA, USA.
authors.forename: Amélie
authors.initials: A
authors.lastname: Boichard
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA; San Diego Supercomputer Center, University of California San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; CureMatch Inc., San Diego, CA, USA.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California San Diego, Moores Cancer Center , La Jolla, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
keywords: APOBEC; PD-1 ligands; cancer; cytidine deaminases; immunotherapy; kataegis; mutation burden