Reprogramming of pancreatic adenocarcinoma immunosurveillance by a microbial probiotic siderophore

作者：Mehdi Chaib, Bilal Bin Hafeez, Hassan Mandil, Deidre Daria, Ajeeth K. Pingili, Sonam Kumari, Mohammed Sikander, Vivek K. Kashyap, Guo‐Yun Chen, Emmanuel Anning, Manish Tripathi, Sheema Khan, Stephen W. Behrman, Murali M. Yallapu, Meena Jaggi, Liza Makowski, Subhash C. Chauhan · 发表于：Communications Biology · 年份：2022 · DOI：10.1038/s42003-022-04102-4 · 被引用次数：18 · 研究领域：Pancreatic and Hepatic Oncology Research、Phagocytosis and Immune Regulation、Cancer Research and Treatments

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.