Department of Surgery, University of Michigan, Ann Arbor, MI.
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI.
J Exp Med. 2023 Jan 2;220(1). doi: 10.1084/jem.20220503. Epub 2022 Oct 14.
Pancreatic ductal adenocarcinoma (PDA) is associated with activation of WNT signaling. Whether this signaling pathway regulates the tumor microenvironment has remained unexplored. Through single-cell RNA sequencing of human pancreatic cancer, we discovered that tumor-infiltrating CD4+ T cells express TCF7, encoding for the transcription factor TCF1. We conditionally inactivated Tcf7 in CD4 expressing T cells in a mouse model of pancreatic cancer and observed changes in the tumor immune microenvironment, including more CD8+ T cells and fewer regulatory T cells, but also compensatory upregulation of PD-L1. We then used a clinically available inhibitor of Porcupine, a key component of WNT signaling, and observed similar reprogramming of the immune response. WNT signaling inhibition has limited therapeutic window due to toxicity, and PD-L1 blockade has been ineffective in PDA. Here, we show that combination targeting reduces pancreatic cancer growth in an experimental model and might benefit the treatment of pancreatic cancer.
胰腺导管腺癌（PDA）与 WNT 信号的激活有关。然而，这条信号通路是否调节肿瘤微环境尚未被探索。通过对人类胰腺癌的单细胞 RNA 测序，我们发现肿瘤浸润的 CD4+T 细胞表达 TCF7，其编码转录因子 TCF1。我们在胰腺癌的小鼠模型中条件性地使表达 TCF7 的 CD4+T 细胞失活，观察到肿瘤免疫微环境发生变化，包括更多的 CD8+T 细胞和更少的调节性 T 细胞，但也伴随着 PD-L1 的代偿性上调。然后，我们使用一种临床可用的 WNT 信号通路关键成分 Porcupine 的抑制剂，观察到免疫反应的类似重编程。由于毒性，WNT 信号抑制的治疗窗口有限，而 PD-L1 阻断在 PDA 中无效。在这里，我们表明联合靶向治疗可减少实验模型中的胰腺癌生长，可能有益于胰腺癌的治疗。
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