Open AccessTumour DDR1 promotes collagen fibre alignment to instigate immune exclusion
Author(s) -
Xiujie Sun,
Bogang Wu,
Huai-Chin Chiang,
Hui Deng,
Xiaowen Zhang,
Wei Xiong,
Junquan Liu,
Aaron M. Rozeboom,
Brent T. Harris,
Eline Blommaert,
Antonio Gómez,
Roderic Espín,
Yufan Zhou,
Payal Mitra,
M. Prevost,
Deyi Zhang,
Debarati Banik,
Claudine Isaacs,
Deborah L. Berry,
Catherine Lai,
Krysta Chaldekas,
Patricia S. Latham,
Christine A. Brantner,
Anastas Popratiloff,
Victor X. Jin,
Ningyan Zhang,
Yanfen Hu,
Miguel Ángel Pujana,
Tyler J. Curiel,
Zhiqiang An,
Rong Li
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-04057-2
Subject(s) - ddr1 , immune system , biology , extracellular matrix , receptor tyrosine kinase , discoidin domain , cancer research , microbiology and biotechnology , immunology , kinase
Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC) 1 . The extracellular matrix (ECM) contributes to immune exclusion 2 . However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes 3,4 . Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity 5 , 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.