TY - JOUR
T1 - Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion
AU - Sun, Xiujie
AU - Wu, Bogang
AU - Chiang, Huai Chin
AU - Deng, Hui
AU - Zhang, Xiaowen
AU - Xiong, Wei
AU - Liu, Junquan
AU - Rozeboom, Aaron M.
AU - Harris, Brent T.
AU - Blommaert, Eline
AU - Gomez, Antonio
AU - Garcia, Roderic Espin
AU - Zhou, Yufan
AU - Mitra, Payal
AU - Prevost, Madeleine
AU - Zhang, Deyi
AU - Banik, Debarati
AU - Isaacs, Claudine
AU - Berry, Deborah
AU - Lai, Catherine
AU - Chaldekas, Krysta
AU - Latham, Patricia S.
AU - Brantner, Christine A.
AU - Popratiloff, Anastas
AU - Jin, Victor X.
AU - Zhang, Ningyan
AU - Hu, Yanfen
AU - Pujana, Miguel Angel
AU - Curiel, Tyler J.
AU - An, Zhiqiang
AU - Li, Rong
N1 - Funding Information:
Acknowledgements We thank S. Hursting for M-Wnt cells, S. Abrams for AT-3 cells, L. Sun for HCC1937 cells, and John R Hawse and Thomas C. Spelsberg for Hs578T cells. We also thank L. Lin for technical assistance in plasmid construction, L. Audoly for discussion, G. T. Salazar for editing the manuscript and X. Zhang for technical assistance with oestrogen receptor and progesterone receptor (ER and PR) immunohistochemistry. The work was supported by grants to R.L. and T.J.C. from the National Institutes of Health (NIH) (CA206529); to R.L. from NIH (CA246707) and the Walter G. Ross Foundation; to T.J.C. from NIH (CA205965) and the Owens Foundation and the Skinner Endowment; to Y.H. from NIH (CA212674); the Congressionally Directed Medical Research Program (W81XWH-17-1-0008); to V.X.J from NIH (GM114142); and to Z.A. from the Cancer Prevention and Research Institute of Texas (RP150551 and RP190561) and the Welch Foundation (AU-0042-20030616). The Genome Sequencing Facility at the UT Health San Antonio is supported by NIH-NCI P30 CA054174 (Mays Cancer Center at UT Health San Antonio), NIH Shared Instrument grant 1S10OD021805-01 (S10 grant), and CPRIT Core Facility Award (RP160732). Georgetown University Medical Center Shared Resources are supported in part by P30 CA051008 (Lombardi Comprehensive Cancer Center Support Grant; Principal Investigator L. Weiner). The ICO-IDIBELL research was supported by the Generalitat de Catalunya (SGR 2017-449; PFI-Salut SLT017-20-000076; and CERCA program) and the Carlos III Institute of Health (ISCIII), funded by FEDER funds (‘A way to build Europe’), grants PI18/01029 and PI21/01306.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/11/25
Y1 - 2021/11/25
N2 - Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
AB - Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
UR - http://www.scopus.com/inward/record.url?scp=85118481803&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118481803&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04057-2
DO - 10.1038/s41586-021-04057-2
M3 - Article
C2 - 34732895
AN - SCOPUS:85118481803
SN - 0028-0836
VL - 599
SP - 673
EP - 678
JO - Nature
JF - Nature
IS - 7886
ER -