TY - JOUR
T1 - Discoidin Domain Receptor-Driven Gene Signatures as Markers of Patient Response to Anti-PD-L1 Immune Checkpoint Therapy
AU - You, Sungyong
AU - Kim, Minhyung
AU - Hoi, Xen Ping
AU - Lee, Yu Cheng
AU - Wang, Li
AU - Spetzler, David
AU - Abraham, Jim
AU - Magee, Dan
AU - Jain, Prerna
AU - Galsky, Matthew D.
AU - Chan, Keith Syson
AU - Theodorescu, Dan
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell-inflamed phenotype, whereas DDR1high 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, DDR2high 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.
AB - 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. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell-inflamed phenotype, whereas DDR1high 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, DDR2high 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.
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U2 - 10.1093/jnci/djac140
DO - 10.1093/jnci/djac140
M3 - Article
C2 - 35918812
AN - SCOPUS:85139572854
SN - 0027-8874
VL - 114
SP - 1380
EP - 1391
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 10
ER -