Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Xiujie Sun, Bogang Wu, Huai-Chin Chiang, Hui Deng, Xiaowen Zhang, Wei Xiong, Junquan Liu, Aaron M. Rozeboom, Brent T. Harris, Eline Blommaert, Antonio Gomez, Roderic Espin Garcia, Yufan Zhou, Payal Mitra, Madeleine Prevost, Deyi Zhang, Debarati Banik, Claudine Isaacs, Deborah Berry, Catherine Lai, Krysta Chaldekas, Patricia S. Latham, Christine A. Brantner, Anastas Popratiloff, Victor X. Jin, Ningyan Zhang, Yanfen Hu, Miguel Angel Pujana (), Tyler J. Curiel (), Zhiqiang An () and Rong Li ()
Additional contact information
Xiujie Sun: The George Washington University
Bogang Wu: The George Washington University
Huai-Chin Chiang: The George Washington University
Hui Deng: The University of Texas Health Science Center at Houston
Xiaowen Zhang: The George Washington University
Wei Xiong: The University of Texas Health Science Center at Houston
Junquan Liu: The University of Texas Health Science Center at Houston
Aaron M. Rozeboom: Georgetown University Medical Center
Brent T. Harris: Georgetown University Medical Center
Eline Blommaert: ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Antonio Gomez: Vall d’Hebron Hospital Research Institute
Roderic Espin Garcia: ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Yufan Zhou: University of Texas Health San Antonio
Payal Mitra: The George Washington University
Madeleine Prevost: The George Washington University
Deyi Zhang: University of Texas Health San Antonio
Debarati Banik: The George Washington University
Claudine Isaacs: Georgetown University Medical Center
Deborah Berry: Georgetown University Medical Center
Catherine Lai: Georgetown University Medical Center
Krysta Chaldekas: Georgetown University Medical Center
Patricia S. Latham: The George Washington University
Christine A. Brantner: The George Washington University
Anastas Popratiloff: The George Washington University
Victor X. Jin: University of Texas Health San Antonio
Ningyan Zhang: The University of Texas Health Science Center at Houston
Yanfen Hu: The George Washington University
Miguel Angel Pujana: ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Tyler J. Curiel: University of Texas Health San Antonio
Zhiqiang An: The University of Texas Health Science Center at Houston
Rong Li: The George Washington University

Nature, 2021, vol. 599, issue 7886, 673-678

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-04057-2

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