Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Autor: Sun X; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Wu B; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Chiang HC; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Deng H; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA., Zhang X; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Xiong W; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA., Liu J; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA., Rozeboom AM; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Harris BT; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Blommaert E; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain., Gomez A; Rheumatology Department and Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain., Garcia RE; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain., Zhou Y; Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA., Mitra P; Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Prevost M; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Zhang D; Department of Medicine, The Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA., Banik D; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Isaacs C; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Berry D; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Lai C; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Chaldekas K; Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA., Latham PS; Department of Pathology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Brantner CA; GW Nanofabrication and Imaging Center, The George Washington University, Washington, DC, USA., Popratiloff A; GW Nanofabrication and Imaging Center, The George Washington University, Washington, DC, USA., Jin VX; Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA., Zhang N; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA., Hu Y; Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA., Pujana MA; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain. mapujana@iconcologia.net., Curiel TJ; Department of Medicine, The Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA. curielt@uthscsa.edu., An Z; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. Zhiqiang.An@uth.tmc.edu., Li R; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA. rli69@gwu.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Nov; Vol. 599 (7886), pp. 673-678. Date of Electronic Publication: 2021 Nov 03.
DOI: 10.1038/s41586-021-04057-2
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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