Title

Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Authors

Xiujie Sun, The George Washington University School of Medicine and Health Sciences
Bogang Wu, The George Washington University School of Medicine and Health Sciences
Huai Chin Chiang, The George Washington University School of Medicine and Health Sciences
Hui Deng, University of Texas Health Science Center at Houston
Xiaowen Zhang, The George Washington University School of Medicine and Health Sciences
Wei Xiong, University of Texas Health Science Center at Houston
Junquan Liu, University of Texas Health Science Center at Houston
Aaron M. Rozeboom, Georgetown Lombardi Comprehensive Cancer Center
Brent T. Harris, Georgetown Lombardi Comprehensive Cancer Center
Eline Blommaert, Institute Catala Oncologia
Antonio Gomez, Vall d'Hebron Institut de Recerca
Roderic Espin Garcia, Institute Catala Oncologia
Yufan Zhou, University of Texas Health Science Center at San Antonio
Payal Mitra, The George Washington University School of Medicine and Health Sciences
Madeleine Prevost, The George Washington University School of Medicine and Health Sciences
Deyi Zhang, Mays Cancer Center
Debarati Banik, The George Washington University School of Medicine and Health Sciences
Claudine Isaacs, Georgetown Lombardi Comprehensive Cancer Center
Deborah Berry, Georgetown Lombardi Comprehensive Cancer Center
Catherine Lai, Georgetown Lombardi Comprehensive Cancer Center
Krysta Chaldekas, Georgetown Lombardi Comprehensive Cancer Center
Patricia S. Latham, The George Washington University School of Medicine and Health Sciences
Christine A. Brantner, The George Washington University
Anastas Popratiloff, The George Washington University
Victor X. Jin, University of Texas Health Science Center at San Antonio
Ningyan Zhang, University of Texas Health Science Center at Houston
Yanfen Hu, The George Washington University School of Medicine and Health Sciences
Miguel Angel Pujana, Institute Catala Oncologia
Tyler J. Curiel, Mays Cancer Center
Zhiqiang An, University of Texas Health Science Center at Houston
Rong Li, The George Washington University School of Medicine and Health Sciences

Document Type

Journal Article

Publication Date

1-1-2021

Journal

Nature

DOI

10.1038/s41586-021-04057-2

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.

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