胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，临床对新疗法的迫切需求尚未得到满足。通过结合体外测定和体内临床前模型，我们证明对 IGF 信号轴的治疗性抑制可促进 PDAC 肿瘤的肿瘤微环境中 CD8 细胞毒性 T 细胞的积累。从机制上讲，我们发现 IGF 阻断可促进巨噬细胞和成纤维细胞产生趋化因子 CXCL9 和 CXCL10，从而促进 CD8 T 细胞招募和运输至 PDAC 肿瘤。进一步探索该通路，我们发现 IGF 抑制导致 STAT1 转录活性增加，与 AKT/STAT3 信号轴下调相关，进而促进 Cxcl9 和 Cxcl10 基因转录。使用患者来源的肿瘤外植体，我们还证明我们的发现可以转化为人类环境。 PDAC 肿瘤经常被描述为“免疫冷”，因此通过 IGF 抑制促进 CD8 T 细胞向 PDAC 肿瘤的募集可能有助于提高依赖于肿瘤中 CD8 T 细胞存在的免疫检查点抑制剂的功效。版权所有 © 2024 Freeman，贝洛莫、爱尔兰、阿布杜拉、卢克特、奥伯斯特、斯塔弗顿、加内、哈洛兰、施密德和米尔戈。

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an urgent unmet clinical need for new therapies. Using a combination of in vitro assays and in vivo preclinical models we demonstrate that therapeutic inhibition of the IGF signalling axis promotes the accumulation of CD8+ cytotoxic T cells within the tumour microenvironment of PDAC tumours. Mechanistically, we show that IGF blockade promotes macrophage and fibroblast production of the chemokines CXCL9 and CXCL10 to facilitate CD8+ T cell recruitment and trafficking towards the PDAC tumour. Exploring this pathway further, we show that IGF inhibition leads to increased STAT1 transcriptional activity, correlating with a downregulation of the AKT/STAT3 signalling axis, in turn promoting Cxcl9 and Cxcl10 gene transcription. Using patient derived tumour explants, we also demonstrate that our findings translate into the human setting. PDAC tumours are frequently described as "immunologically cold", therefore bolstering CD8+ T cell recruitment to PDAC tumours through IGF inhibition may serve to improve the efficacy of immune checkpoint inhibitors which rely on the presence of CD8+ T cells in tumours.Copyright © 2024 Freeman, Bellomo, Ireland, Abudula, Luckett, Oberst, Stafferton, Ghaneh, Halloran, Schmid and Mielgo.