Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

• Published in: Nature (London) 2021-11, Vol.599 (7886), p.673-678
• Main Authors: Sun, Xiujie, Wu, Bogang, Chiang, Huai-Chin, Deng, Hui, Zhang, Xiaowen, Xiong, Wei, Liu, Junquan, Rozeboom, Aaron M., Harris, Brent T., Blommaert, Eline, Gomez, Antonio, Garcia, Roderic Espin, Zhou, Yufan, Mitra, Payal, Prevost, Madeleine, Zhang, Deyi, Banik, Debarati, Isaacs, Claudine, Berry, Deborah, Lai, Catherine, Chaldekas, Krysta, Latham, Patricia S., Brantner, Christine A., Popratiloff, Anastas, Jin, Victor X., Zhang, Ningyan, Hu, Yanfen, Pujana, Miguel Angel, Curiel, Tyler J., An, Zhiqiang, Li, Rong
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/44; 13/51; 14; 14/19; 14/63; 38; 38/39; 38/70; 38/77; 38/90; 42; 42/41; 45; 59; 631/67/1347; 631/67/327; 64; 64/60; 82; 82/29; 82/51; 82/80; 82/83; 96; 96/21; 96/31; 96/95; Ablation; Alignment; Animal models; Animals; Antibodies; Breast cancer; Cell Line, Tumor; Collagen; Collagen - metabolism; Discoidin Domain Receptor 1 - antagonists & inhibitors; Discoidin Domain Receptor 1 - deficiency; Discoidin Domain Receptor 1 - genetics; Discoidin Domain Receptor 1 - metabolism; Disease Models, Animal; Domains; Extracellular matrix; Extracellular Matrix - immunology; Extracellular Matrix - metabolism; Female; Fibers; Gene Deletion; Gene expression; Gene Knockout Techniques; Genetic aspects; Health aspects; Humanities and Social Sciences; Humans; Immune response; Immunocompetence; Immunocompetence - immunology; Immunotherapy; Kinases; Lymphocytes; Lymphocytes T; Metastases; Mice; multidisciplinary; Physiological aspects; Protein-tyrosine kinase; Receptors; Reconfiguration; Science; Science (multidisciplinary); Signal transduction; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - therapy; Tumor Escape; Tumors; Tyrosine
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-04057-2

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. In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration.