Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Nature. 2021 Nov;599(7886):673-678. doi: 10.1038/s41586-021-04057-2. Epub 2021 Nov 3.
Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC). The extracellular matrix (ECM) contributes to immune exclusion. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity, 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.
免疫排斥预测多种恶性肿瘤（包括三阴性乳腺癌 [TNBC]）患者预后不良。细胞外基质（ECM）有助于免疫排斥。然而，减少 ECM 丰度的策略在很大程度上是无效的或产生不良后果。在这里，我们表明具有酪氨酸激酶活性的胶原受体 discoidin 域受体 1（DDR1）通过促进胶原纤维排列引发免疫排斥。在肿瘤中敲除 Ddr1 可促进 T 细胞在肿瘤内的浸润，并在 TNBC 的小鼠模型中消除肿瘤生长。支持这一发现，在人类 TNBC 中，DDR1 的表达与肿瘤内抗肿瘤 T 细胞的丰度呈负相关。DDR1 的细胞外结构域（DDR1-ECD），而不是其细胞内激酶结构域，是免疫排斥所必需的。膜非束缚的 DDR1-ECD 足以挽救 DDR1 敲除肿瘤在免疫活性宿主中的生长。从机制上讲，DDR1-ECD 与胶原的结合强制形成排列整齐的胶原纤维，并阻碍免疫浸润。ECD 中和抗体破坏胶原纤维排列，减轻免疫排斥并抑制免疫活性宿主中的肿瘤生长。总之，我们的研究结果确定了一种免疫排斥的机制，并提出了一种通过重新配置肿瘤 ECM 来增加免疫可及性的免疫治疗靶标。
