TY - JOUR
T1 - Commensal bacterial hybrid nanovesicles improve immune checkpoint therapy in pancreatic cancer through immune and metabolic reprogramming
AU - Liu, Guangnian
AU - Huang, Wenping
AU - Chen, Lin
AU - Tayier, Nilupaier
AU - You, Liwei
AU - Hamza, Muhammad
AU - Tian, Xiaodong
AU - Wang, Hai
AU - Nie, Guangjun
AU - Zhu, Motao
AU - Yang, Yinmo
N1 - Funding Information:
This work was supported by grants from the National Key R&D Program of China (2021YFA1201100, 2022YFA1206100, 2021YFA0909900), the National Natural Science Foundation of China (32271449, 81871954, 82171722, 82271764), CAS Project for Young Scientists in Basic Research (YSBR-036), Beijing Municipal Natural Science Foundation (7212111). We thank P. Li (National Center for Nanoscience and Technology) for assistance with flow cytometry. We thank Y. Wu (State Key Laboratory of Plant Genomics, Institute of Microbiology, Chinese Academy of Science) for assistance in mass spectrometry. We also thank P. Jiao (Core Facility of Center of Biomedical Analysis, Tsinghua University) for assistance with measurement of oxygen consumption rates.
Funding Information:
This work was supported by grants from the National Key R&D Program of China ( 2021YFA1201100 , 2022YFA1206100 , 2021YFA0909900 ), the National Natural Science Foundation of China ( 32271449 , 81871954 , 82171722 , 82271764 ), CAS Project for Young Scientists in Basic Research ( YSBR-036 ), Beijing Municipal Natural Science Foundation ( 7212111 ). We thank P. Li (National Center for Nanoscience and Technology) for assistance with flow cytometry. We thank Y. Wu (State Key Laboratory of Plant Genomics, Institute of Microbiology, Chinese Academy of Science) for assistance in mass spectrometry. We also thank P. Jiao (Core Facility of Center of Biomedical Analysis, Tsinghua University) for assistance with measurement of oxygen consumption rates.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/10
Y1 - 2023/10
N2 - Harnessing the immunomodulatory ability of the microbiota, such as fecal microbiota transplantation (FMT), has emerged as a promising strategy to improve cancer immunotherapy. However, the lack of standardization in fecal material formulation and safety concerns have hindered clinical application. To overcome these limitations, we developed a high-yielding method by hybridizing bacteria protoplast-derived membrane nanovesicles (PDNVs) from three colon bacteria strains that have been associated with favorable responses to immune checkpoint therapy, including Akkermansia muciniphila, Bifidobacterium longum, and Bifidobacterium breve. The resulting hybrid nanovesicles (HNVs) are composed mainly of cytoplasmic membrane proteins inherited from the originating bacteria but lack pyrogens such as lipopolysaccharide and lipoteichoic acid. Our study demonstrated that HNVs have superior targeting abilities to tumors and peripheral lymphoid organs, leading to greater capability in inducing innate immune activation, dendritic cell maturation and antigen presentation, as well as tumor microenvironment reprogramming. Combined with αPD-1 blockade therapy, HNVs efficiently inhibited the tumor growth in multiple pancreatic cancer mouse models, including Panc02 subcutaneous and liver metastatic models, and orthotopic KPC-Luc pancreatic cancer model. Mechanically, HNVs simultaneously activated the innate arm of immunity and inhibited tumor oxidative phosphorylation (OXPHOS) to reshape the tumor immune microenvironment for improved αPD-1 blockade therapy. Notably, HNVs administration gave rise to similar tumor regression rates to oral transfer of a mixture of live or inactivated bacteria during αPD-1 blockade therapy, but with fewer adverse effects such as diarrhea and colon-intestinal inflammation. Our findings present a stable, cost-effective, and safe alternative to live bacteria for regulating tumor microenvironment for improved cancer immunotherapy.
AB - Harnessing the immunomodulatory ability of the microbiota, such as fecal microbiota transplantation (FMT), has emerged as a promising strategy to improve cancer immunotherapy. However, the lack of standardization in fecal material formulation and safety concerns have hindered clinical application. To overcome these limitations, we developed a high-yielding method by hybridizing bacteria protoplast-derived membrane nanovesicles (PDNVs) from three colon bacteria strains that have been associated with favorable responses to immune checkpoint therapy, including Akkermansia muciniphila, Bifidobacterium longum, and Bifidobacterium breve. The resulting hybrid nanovesicles (HNVs) are composed mainly of cytoplasmic membrane proteins inherited from the originating bacteria but lack pyrogens such as lipopolysaccharide and lipoteichoic acid. Our study demonstrated that HNVs have superior targeting abilities to tumors and peripheral lymphoid organs, leading to greater capability in inducing innate immune activation, dendritic cell maturation and antigen presentation, as well as tumor microenvironment reprogramming. Combined with αPD-1 blockade therapy, HNVs efficiently inhibited the tumor growth in multiple pancreatic cancer mouse models, including Panc02 subcutaneous and liver metastatic models, and orthotopic KPC-Luc pancreatic cancer model. Mechanically, HNVs simultaneously activated the innate arm of immunity and inhibited tumor oxidative phosphorylation (OXPHOS) to reshape the tumor immune microenvironment for improved αPD-1 blockade therapy. Notably, HNVs administration gave rise to similar tumor regression rates to oral transfer of a mixture of live or inactivated bacteria during αPD-1 blockade therapy, but with fewer adverse effects such as diarrhea and colon-intestinal inflammation. Our findings present a stable, cost-effective, and safe alternative to live bacteria for regulating tumor microenvironment for improved cancer immunotherapy.
KW - Gut microbiota
KW - Hybrid nanovesicles
KW - Immune checkpoint inhibitors
KW - Pancreatic ductal adenocarcinoma
KW - Tumor microenvironment reprogramming
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U2 - 10.1016/j.nantod.2023.101993
DO - 10.1016/j.nantod.2023.101993
M3 - Article
AN - SCOPUS:85170414045
SN - 1748-0132
VL - 52
JO - Nano Today
JF - Nano Today
M1 - 101993
ER -