Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses

Menglin Wang; Benoit Rousseau; Kunyu Qiu; Guannan Huang; Yu Zhang; Hang Su; Christine Le Bihan-Benjamin; Ines Khati; Oliver Artz; Michael B Foote; Yung-Yi Cheng; Kuo-Hsiung Lee; Michael Z Miao; Yue Sun; Philippe-Jean Bousquet; Marc Hilmi; Elise Dumas; Anne-Sophie Hamy; Fabien Reyal; Lin Lin; Paul M Armistead; Wantong Song; Ava Vargason; Janelle C Arthur; Yun Liu; Jianfeng Guo; Xuefei Zhou; Juliane Nguyen; Yongqun He; Jenny P-Y Ting; Aaron C Anselmo; Leaf Huang

doi:10.1038/s41587-023-01957-8

Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses

Nat Biotechnol. 2023 Sep 25. doi: 10.1038/s41587-023-01957-8. Online ahead of print.

Authors

Menglin Wang¹, Benoit Rousseau², Kunyu Qiu¹, Guannan Huang^{3

4

5}, Yu Zhang¹, Hang Su⁶, Christine Le Bihan-Benjamin⁷, Ines Khati⁷, Oliver Artz², Michael B Foote², Yung-Yi Cheng⁸, Kuo-Hsiung Lee^{8

9}, Michael Z Miao^{10

11}, Yue Sun¹², Philippe-Jean Bousquet¹³, Marc Hilmi^{14

15}, Elise Dumas^{16

17

18}, Anne-Sophie Hamy^{16

19}, Fabien Reyal^{16

20

21}, Lin Lin²², Paul M Armistead^{22

23}, Wantong Song^{24

25}, Ava Vargason¹, Janelle C Arthur^{3

5

26}, Yun Liu¹, Jianfeng Guo¹, Xuefei Zhou¹, Juliane Nguyen¹, Yongqun He^{27

28

29}, Jenny P-Y Ting^{3

4

5

30}, Aaron C Anselmo¹, Leaf Huang³¹

Affiliations

¹ Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
² Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁵ Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
⁶ Department of Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
⁷ Health Data and Assessment Department, Data Science and Assessment Division, French National Cancer Institute, Boulogne-Billancourt, France.
⁸ Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
⁹ Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
¹⁰ Curriculum in Oral and Craniofacial Biomedicine, Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina, Chapel Hill, NC, USA.
¹¹ Thurston Arthritis Research Center, Division of Rheumatology, Allergy, and Immunology, University of North Carolina, Chapel Hill, NC, USA.
¹² Department of Radiology and Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA.
¹³ Health Survey, Data Science and Assessment Division, French National Cancer Institute, Boulogne Billancourt, France.
¹⁴ GERCOR Group, Paris, France.
¹⁵ Medical Oncology Department, Curie Institute, Saint Cloud, France.
¹⁶ Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, Paris, France.
¹⁷ INSERM, U900, Paris, France.
¹⁸ MINES ParisTech, PSL Research University, CBIO-Centre for Computational Biology, Paris, France.
¹⁹ Department of Medical Oncology, Centre René Hughenin, Saint Cloud, France.
²⁰ Department of Surgery, Institut Jean Godinot, Reims, France.
²¹ Department of Surgical Oncology, Institut Curie, University of Paris, Paris, France.
²² BMTCT Program, Division of Hematology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
²³ Department of Internal Medicine, University of North Carolina, Chapel Hill, NC, USA.
²⁴ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
²⁵ Jilin Biomedical Polymers Engineering Laboratory, Changchun, China.
²⁶ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
²⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
²⁸ Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
²⁹ Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
³⁰ Division of Craniofacial and Surgical Care, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³¹ Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA. leafh@email.unc.edu.

PMID: 37749267
DOI: 10.1038/s41587-023-01957-8

Abstract

Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp.) or probiotics (Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum-infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8⁺ T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome-immunotherapy interventions.

Abstract

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