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

Background

 

Anti–programmed cell death 1 (anti–PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to predict nonresponders 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 whether this gene family may provide ICT response prediction.

 

Methods

 

We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (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–The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR_–_driven signatures to predict ICT response was 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. _DDR2_high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell–inflamed phenotype, whereas _DDR1_high BCa exhibited a non–T-cell–inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, _DDR2_high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P < .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets.

 

Conclusions

 

These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response.