Background Discoidin Domain Receptor 1 (DDR1) is a tyrosine kinase expressed on cancer cells that binds to collagen, is associated with T-cell exclusion and poor outcomes in several cancer types and is the target of investigational drug therapy PRTH-101.1 2 DDR1 mRNA expression is known to be high in intrahepatic cholangiocarcinoma (iCCA). We evaluated the correlation of DDR1 protein expression with histologic and clinicopathologic factors and outcomes in iCCA.
Methods Surgical samples from 80 patients with iCCA who underwent resection at a single institution from 2004–2016 were evaluated by multiplexed immunofluorescence (mIF) and DDR1 immunohistochemisty (IHC) in a tissue microarray.3 IHC and mIF values across multiple samples from the same tumor were averaged for each of the patients. DDR1 was classified as high for an H score >150. Correlations between DDR1 H-score and clinicopathologic features and outcomes were compared using Spearman correlation (continuous variables), Wilcoxon Rank sum (binary features), or Kruskal-Wallis tests (categorical features).
Results DDR1 expression was high in 87.5% (70/80) of iCCA. There was IHC 3+ expression on 100% of cells in 25% (20/80) of iCCA. The DDR1 H score was positively correlated with the percentage of the tumor bed that was comprised of stroma (R=0.27, p=0.014). Patients with perineural invasion (n=15) had higher DDR1 H scores (median 292.5, interquartile range 52.5) than patients without (n=65, median 240, interquartile range 105; p=0.011). High DDR1 expression was associated with worse overall survival (0.048) and a trend towards worse disease-free survival (p=0.059), independent of stage. There was no association between DDR1 H-score and CD3+ or CD8+ density within the tumor stroma or parenchyma. There was no association between DDR1 H-score and tumor mutation status, including FGFR and IDH1.
Conclusions DDR1 is highly expressed in the majority of iCCAs. DDR1 expression is associated with higher levels of stroma, which contains collagen, the ligand of DDR1. The prevalence of high DDR1 expression and poor survival outcomes associated with this make iCCA a relevant tumor type for evaluating novel DDR1-targeted therapies.
Sun X, Wu B, Chiang HC, Deng H, Zhang X, Xiong W, Liu J, Rozeboom AM, Harris BT, Blommaert E, Gomez A, Garcia RE, Zhou Y, Mitra P, Prevost M, Zhang D, Banik D, Isaacs C, Berry D, Lai C, Chaldekas K, Latham PS, Brantner CA, Popratiloff A, Jin VX, Zhang N, Hu Y, Pujana MA, Curiel TJ, An Z, Li R. Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion. Nature. 2021 Nov;599(7886):673–678.
Liu J, Chiang HC, Xiong W, Laurent V, Griffiths SC, Dülfer J, Deng H, Sun X, Yin YW, Li W, Audoly LP, An Z, Schürpf T, Li R, Zhang N. A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer. J Immunother Cancer. 2023 Jun;11(6):e006720.
Carapeto F, Bozorgui B, Shroff RT, Chagani S, Solis Soto L, Foo WC, Wistuba I, Meric-Bernstam F, Shalaby A, Javle M, Korkut A, Kwong LN. The immunogenomic landscape of resected intrahepatic cholangiocarcinoma. Hepatology. 2022 Feb;75(2):297–308.
Ethics Approval Informed consent was obtained from all patients involved and was approved by the MD Anderson Cancer Center Institutional Review Board, # PA16–0723
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.