Daley Donnele, Mani Vishnu R, Mohan Navyatha, Akkad Neha, Ochi Atsuo, Heindel Daniel W, Lee Ki Buom, Zambirinis Constantinos P, Pandian Gautam Sd Balasubramania, Savadkar Shivraj, Torres-Hernandez Alejandro, Nayak Shruti, Wang Ding, Hundeyin Mautin, Diskin Brian, Aykut Berk, Werba Gregor, Barilla Rocky M, Rodriguez Robert, Chang Steven, Gardner Lawrence, Mahal Lara K, Ueberheide Beatrix, Miller George
S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York, USA.
Department of Chemistry, New York University, New York, New York, USA.
Nat Med. 2017 May;23(5):556-567. doi: 10.1038/nm.4314. Epub 2017 Apr 10.
The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4 and CD8 T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.
胰腺肿瘤发生的进展需要与致癌突变协同作用的免疫抑制性炎症。然而，肿瘤内免疫耐受的驱动因素尚不确定。Dectin 1是一种对抗真菌免疫至关重要的固有免疫受体，但其在无菌性炎症和肿瘤发生中的作用尚未明确界定。此外，尚未对Dectin 1的非病原体衍生配体进行表征。我们发现Dectin 1在胰腺导管腺癌（PDA）的巨噬细胞上高度表达。Dectin 1连接加速了小鼠PDA的进展，而编码Dectin 1的基因Clec7a的缺失或Dectin 1下游信号传导的阻断具有保护作用。我们发现Dectin 1可以在小鼠和人类PDA中连接凝集素半乳凝素9，这导致耐受性巨噬细胞编程和适应性免疫抑制。在破坏Dectin 1-半乳凝素9轴后，在具有完整信号轴的宿主中对PDA进展而言可有可无的CD4和CD8 T细胞被重新编程为抗肿瘤免疫的不可或缺的介质。这些数据表明，靶向Dectin 1信号传导是开发PDA免疫疗法的有吸引力的策略。
