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Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

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 outcomes^3,4. 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.

SUBMITTER: Sun X

PROVIDER: S-EPMC8839149 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Sun Xiujie X Wu Bogang B Chiang Huai-Chin HC Deng Hui H Zhang Xiaowen X Xiong Wei W Liu Junquan J Rozeboom Aaron M AM Harris Brent T BT Blommaert Eline E Gomez Antonio A Garcia Roderic Espin RE Zhou Yufan Y Mitra Payal P Prevost Madeleine M Zhang Deyi D Banik Debarati D Isaacs Claudine C Berry Deborah D Lai Catherine C Chaldekas Krysta K Latham Patricia S PS Brantner Christine A CA Popratiloff Anastas A Jin Victor X VX Zhang Ningyan N Hu Yanfen Y Pujana Miguel Angel MA Curiel Tyler J TJ An Zhiqiang Z Li Rong R

Nature 20211103 7886

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 ali ...[more]

PMID: 34732895

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Project description:BackgroundCancers aggressively reorganize collagen in their microenvironment, leading to the evasion of tumor cells from immune surveillance. However, the biological significance and molecular mechanism of collagen alignment in breast cancer (BC) have not been well established.MethodsIn this study, BC-related RNA-Seq data were obtained from the TCGA database to analyze the correlation between DDR1 and immune cells. Mouse BC cells EO771 were selected for in vitro validation, and dual-luciferase experiments were conducted to examine the effect of TFAP2A on DDR1 promoter transcription activity. ChIP experiments were performed to assess TFAP2A enrichment on the DDR1 promoter, while Me-RIP experiments were conducted to detect TFAP2A mRNA m6A modification levels, and PAR-CLIP experiments were conducted to determine VIRMA's binding to TFAP2A mRNA and RIP experiments to investigate HNRNPC's recognition of m6A modification on TFAP2A mRNA. Additionally, an in vivo mouse BC transplant model and the micro-physiological system was constructed for validation, and Masson staining was used to assess collagen fiber arrangement. Immunohistochemistry was conducted to identify the number of CD8-positive cells in mouse BC tumors and Collagen IV content in ECM, while CD8 + T cell migration experiments were performed to measure CD8 + T cell migration.ResultsBioinformatics analysis showed that DDR1 was highly expressed in BC and negatively correlated with the proportion of anti-tumor immune cell infiltration. In vitro cell experiments indicated that VIRMA, HNRNPC, TFAP2A, and DDR1 were highly expressed in BC cells. In addition, HNRNPC promoted TFAP2A expression and, therefore, DDR1 transcription by recognizing the m6A modification of TFAP2A mRNA by VIRMA. In vivo animal experiments further confirmed that VIRMA and HNRNPC enhanced the TFAP2A/DDR1 axis, promoting collagen fiber alignment, reducing anti-tumor immune cell infiltration, and promoting immune escape in BC.ConclusionThis study demonstrated that HNRNPC promoted DDR1 transcription by recognizing VIRMA-unveiled m6A modification of TFAP2A mRNA, which enhanced collagen fiber alignment and ultimately resulted in the reduction of anti-tumor immune cell infiltration and promotion of immune escape in BC.

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Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

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Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

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