Zhang Shaopeng, Xu Ximo, Zhang Kundong, Lei Changzheng, Xu Yitian, Zhang Pengshan, Zhang Yuan, Gu Haitao, Huang Chen, Qiu Zhengjun
Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of General Surgery, Jiuquan Branch of Shanghai General Hospital, Jiuquan, Gansu, China.
Cancer Immunol Immunother. 2024 Dec 30;74(1):37. doi: 10.1007/s00262-024-03898-w.
Abundant infiltration of tumor-associated macrophages (TAMs) within the tumor stroma plays a pivotal role in inducing immune escape in pancreatic cancer (PC). Lactate serves as a direct regulator of macrophage polarization and functions, although the precise regulation mechanism remains inadequately understood. Our study revealed that PC cells (PCs) promote macrophage polarization toward M2d through high lactate secretion. M2d is characterized by elevated secretion of IL-10 and VEGF-A, which diminish CD8T cells cytotoxicity and promote tumor neoangiogenesis simultaneously. Additionally, we identify 2,5'-oligoadenylate synthase 3 (OAS3) as an essential regulator of M2d polarization, upregulated by PCs via lactate/METTL3/OAS3 axis. Increased OAS3 expression in TAMs correlates with m6A modification mediated by METTL3 on OAS3 mRNA and is associated with poorer prognosis in PC patients. OAS3 deficiency in macrophages substantially impairs IL-10VEGF-AM2d polarization and their pro-tumor functions while enhancing the therapeutic efficacy of gemcitabine and anti-PD-L1 mAb in humanized mouse models. In conclusion, OAS3 presents as a promising immune therapeutic target for reversing IL-10VEGF-AM2d infiltration and restoring CD8T cell-mediated anti-tumor immunity in pancreatic cancer.
肿瘤相关巨噬细胞（TAMs）在肿瘤基质中的大量浸润在胰腺癌（PC）诱导免疫逃逸中起关键作用。乳酸作为巨噬细胞极化和功能的直接调节因子，尽管其精确调控机制仍未完全阐明。我们的研究表明，胰腺癌细胞（PCs）通过高乳酸分泌促进巨噬细胞向M2d极化。M2d的特征是白细胞介素-10（IL-10）和血管内皮生长因子A（VEGF-A）分泌增加，这会同时降低CD8 + T细胞的细胞毒性并促进肿瘤新生血管形成。此外，我们确定2,5'-寡腺苷酸合成酶3（OAS3）是M2d极化的关键调节因子，PCs通过乳酸/甲基转移酶样3（METTL3）/OAS3轴使其上调。TAMs中OAS3表达的增加与METTL3介导的OAS3 mRNA的N6-甲基腺苷（m6A）修饰相关，并与PC患者较差的预后相关。巨噬细胞中OAS3的缺乏显著损害IL-10 / VEGF-A / M2d极化及其促肿瘤功能，同时增强吉西他滨和抗程序性死亡受体配体1（PD-L1）单克隆抗体在人源化小鼠模型中的治疗效果。总之，OAS3是一个有前景的免疫治疗靶点，可逆转IL-10 / VEGF-A / M2d浸润并恢复胰腺癌中CD8 + T细胞介导的抗肿瘤免疫。
