Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center (UTHSC), Memphis, TN, 38163, USA.
Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
Commun Biol. 2022 Nov 4;5(1):1181. doi: 10.1038/s42003-022-04102-4.
There is increasing evidence suggesting the role of microbiome alterations in relation to pancreatic adenocarcinoma and tumor immune functionality. However, molecular mechanisms of the interplay between microbiome signatures and/or their metabolites in pancreatic tumor immunosurveillance are not well understood. We have identified that a probiotic strain (Lactobacillus casei) derived siderophore (ferrichrome) efficiently reprograms tumor-associated macrophages (TAMs) and increases CD8 + T cell infiltration into tumors that paralleled a marked reduction in tumor burden in a syngeneic mouse model of pancreatic cancer. Interestingly, this altered immune response improved anti-PD-L1 therapy that suggests promise of a novel combination (ferrichrome and immune checkpoint inhibitors) therapy for pancreatic cancer treatment. Mechanistically, ferrichrome induced TAMs polarization via activation of the TLR4 pathway that represses the expression of iron export protein ferroportin (FPN1) in macrophages. This study describes a novel probiotic based molecular mechanism that can effectively induce anti-tumor immunosurveillance and improve immune checkpoint inhibitors therapy response in pancreatic cancer.
越来越多的证据表明，微生物组的改变与胰腺腺癌和肿瘤免疫功能有关。然而，微生物组特征及其代谢物在胰腺肿瘤免疫监视中的相互作用的分子机制尚不清楚。我们已经发现，一种益生菌菌株（干酪乳杆菌）衍生的铁载体（高铁血红素）能够有效地重编程肿瘤相关巨噬细胞（TAMs），并增加 CD8+T 细胞浸润肿瘤，这与胰腺癌的同种异体小鼠模型中的肿瘤负担明显减少相平行。有趣的是，这种改变的免疫反应改善了抗 PD-L1 治疗，这表明一种新的联合（高铁血红素和免疫检查点抑制剂）治疗胰腺癌的前景。从机制上讲，高铁血红素通过激活 TLR4 途径诱导 TAMs 极化，从而抑制巨噬细胞中铁输出蛋白铁蛋白（FPN1）的表达。本研究描述了一种新的基于益生菌的分子机制，可有效诱导抗肿瘤免疫监视，并改善胰腺癌中免疫检查点抑制剂治疗的反应。
