CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer.
WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer.
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胰腺导管腺癌（PDA）与WNT信号通路的激活相关。该信号通路是否调控肿瘤微环境尚未被探索。通过对人胰腺癌的单细胞RNA测序，我们发现肿瘤浸润性CD4+ T细胞表达TCF7，其编码转录因子TCF1。我们在胰腺癌小鼠模型的CD4表达T细胞中条件性失活Tcf7，观察到肿瘤免疫微环境的变化，包括CD8+ T细胞增多和调节性T细胞减少，但也出现了PD-L1的代偿性上调。随后我们使用了一种临床可用的Porcupine抑制剂——Porcupine是WNT信号通路的关键组分——并观察到类似的免疫应答重编程。WNT信号通路抑制由于毒性而治疗窗口有限，而PD-L1阻断在PDA中一直无效。在此，我们表明联合靶向治疗在实验模型中减少了胰腺癌生长，可能有益于胰腺癌的治疗。
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.
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