美国乔治华盛顿大学Rong Li、美国休斯顿德克萨斯大学Zhiqiang An、美国德克萨斯大学Tyler J. Curiel以及西班牙Bellvitge 生物医学研究所 (IDIBELL)Miguel Angel Pujana研究组合作取得最新进展。他们发现肿瘤盘状蛋白结构域受体 1（DDR1）促进胶原纤维排列以激发免疫排斥。该研究于2021年11月3日发表于国际一流学术期刊《自然》杂志上。

他们表明DDR1通过促进胶原纤维排列来激发免疫排斥，DDR1是一种具有酪氨酸激酶活性的胶原受体。肿瘤中 Ddr1 的消融促进 T 细胞的肿瘤内渗透并消除三阴性乳腺癌 (TNBC)小鼠模型中的肿瘤生长。支持这一发现的是，在人类 TNBC 中，DDR1 的表达与抗肿瘤 T 细胞的瘤内丰度呈负相关。DDR1 细胞外结构域 (DDR1-ECD) 是免疫排斥所必需的，但其细胞内激酶结构域不是。不受膜限制的 DDR1-ECD 足以挽救免疫活性宿主中 Ddr1 基因敲除肿瘤的生长。

从机制上讲，DDR1-ECD 与胶原蛋白的结合使胶原纤维排列整齐并阻碍免疫浸润。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，他们的发现确定了一种免疫排斥机制，并提出了一种通过重新配置肿瘤细胞外基质 (ECM)来增加免疫可及性的免疫治疗靶点。

研究人员表示，免疫排斥可预测多种恶性肿瘤患者的不良预后，包括TNBC。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预后。

附：英文原文

Title: Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Author: 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

Issue&Volume: 2021-11-03

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 outcomes3,4. Here we show that discoidin domain receptor1 (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.

DOI: 10.1038/s41586-021-04057-2

Source: https://www.nature.com/articles/s41586-021-04057-2