Discoidin Domain Receptor-Driven Gene Signatures as Markers of Patient Response to Anti–PD-L1 Immune Checkpoint Therapy

Abstract

Background Anti-PD-1/PD-L1 immune checkpoint therapies (ICTs) only provided durable responses in a subset of cancer patients. Thus, biomarkers are needed to predict non-responders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti-PD-1 resistance in animal models; therefore, we sought to investigate if this gene family may provide ICT response prediction. Methods We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of BCa models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa TCGA (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses were performed. The potential of DDR-driven signatures to predict ICT response were evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided. Results DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high “immune score”, indicative of a T-cell-inflamed phenotype, while DDR1high BCa exhibited a non-T-cell-inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (HR = 1.53 95% CI = [1.16–2.06], P=.003) or DDR2 (HR = 1.42 95% CI = [1.01–1.92], P=.04) scores had poor overall survival (OS). Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer OS (HR = 1.56 95% CI = [1.20–2.06], P<.001) and progression-free survival (HR = 1.77 95% CI = [1.05–3.00], P=.047), respectively. This was validated in independent cancer datasets. Conclusions These findings implicate DDR1/2-driven signature scores in predicting ICT response.

Identifying novel biomarkers associated with bladder cancer treatment outcomes

“…High expression of DDR2 indicated a T-cell inflamed phenotype whereas high levels of DDR1 indicated a non-inflamed phenotype. Furthermore, DDR signature score was developed which predicted overall survival in two independent cohorts undergoing ICI therapy ( 87 ). These studies offer a potential way to stratify ICI responders based on multi-gene expression signatures.…”