DietaryLactobacillus-Derived Exopolysaccharide Enhances Immune-Checkpoint Blockade Therapy

Author:

Kawanabe-Matsuda Hirotaka12ORCID,Takeda Kazuyoshi13ORCID,Nakamura Marie2,Makino Seiya12,Karasaki Takahiro45ORCID,Kakimi Kazuhiro4ORCID,Nishimukai Megumi6ORCID,Ohno Tatsukuni178ORCID,Omi Jumpei91011,Kano Kuniyuki91011ORCID,Uwamizu Akiharu91011ORCID,Yagita Hideo12,Boneca Ivo Gomperts13ORCID,Eberl Gérard14,Aoki Junken91011ORCID,Smyth Mark J.15,Okumura Ko116

Affiliation:

1. 1Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

2. 2Research Team, Co-Creation Center, Meiji Holdings Co., Ltd., Hachioji, Japan.

3. 3Laboratory of Cell Biology, Research Support Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

4. 4Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.

5. 5Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

6. 6Department of Animal Science, Faculty of Agriculture, Iwate University, Morioka, Japan.

7. 7Oral Health Science Center, Tokyo Dental College, Tokyo, Japan.

8. 8Tokyo Dental College Research Branding Project, Tokyo Dental College, Tokyo, Japan.

9. 9Department of Health Chemistry, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.

10. 10Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Japan.

11. 11AMED-LEAP, Japan Science and Technology Corporation, Kawaguchi, Japan.

12. 12Department of Immunology, School of Medicine, Juntendo University, Tokyo, Japan.

13. 13Institut Pasteur, Unit of Biology and Genetics of Bacterial Cell Wall, Paris, France. INSERM, Équipe Avenir, Paris, France.

14. 14Microenvironment and Immunity Unit, Institut Pasteur, Paris, France.

15. 15Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

16. 16Atopy (Allergy) Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Abstract

AbstractMicrobes and their byproducts have been reported to regulate host health and immune functions. Here we demonstrated that microbial exopolysaccharide produced by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 (EPS-R1) induced CCR6+ CD8+ T cells of mice and humans. In mice, ingestion of EPS-R1 augmented antitumor effects of anti–CTLA-4 or anti–PD-1 monoclonal antibody against CCL20-expressing tumors, in which infiltrating CCR6+ CD8+ T cells were increased and produced IFNγ accompanied by a substantial immune response gene expression signature maintaining T-cell functions. Of note, the antitumor adjuvant effect of EPS-R1 was also observed in germ-free mice. Furthermore, the induction of CCR6 expression was mediated through the phosphorylated structure in EPS-R1 and a lysophosphatidic acid receptor on CD8+ T cells. Overall, we find that dietary EPS-R1 consumption induces CCR6+ CD8+ T cells in Peyer's patches, favoring a tumor microenvironment that augments the therapeutic effect of immune-checkpoint blockade depending on CCL20 production by tumors.Significance:Gut microbiota- and probiotic-derived metabolites are attractive agents to augment the efficacy of immunotherapies. Here we demonstrated that dietary consumption of Lactobacillus-derived exopolysaccharide induced CCR6+ CD8+ T cells in Peyer's patches and improved the tumor microenvironment to augment the therapeutic effects of immune-checkpoint blockade against CCL20-producing tumors.See related commentary by Di Luccia and Colonna, p. 1189.This article is highlighted in the In This Issue feature, p. 1171

Funder

Ministry of Education, Culture, Sports, Science and Technology

Japan Agency for Medical Research and Development

National Health and Medical Research Council

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology

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