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Combining an alarmin HMGN1 peptide with PD-L1 blockade facilitates stem-like CD8+ T cell expansion and results in robust antitumor effects

View ORCID ProfileChang-Yu Chen, Satoshi Ueha, Yoshiro Ishiwata, View ORCID ProfileShigeyuki Shichino, Shoji Yokochi, De Yang, View ORCID ProfileJoost J. Oppenheim, Haru Ogiwara, Shungo Deshimaru, View ORCID ProfileYuzuka Kanno, Tatsuro Ogawa, Shiro Shibayama, Kouji Matsushima
doi: https://doi.org/10.1101/2020.12.15.422990
Chang-Yu Chen
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • ORCID record for Chang-Yu Chen
Satoshi Ueha
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Yoshiro Ishiwata
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Shigeyuki Shichino
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • ORCID record for Shigeyuki Shichino
Shoji Yokochi
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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De Yang
3Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
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Joost J. Oppenheim
3Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA
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  • ORCID record for Joost J. Oppenheim
Haru Ogiwara
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Shungo Deshimaru
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Yuzuka Kanno
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
4Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
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Tatsuro Ogawa
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
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Shiro Shibayama
5Research Center of Immunology, Tsukuba Institute, ONO Pharmaceutical Co., Ltd., Tsukuba, Japan
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Kouji Matsushima
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
2Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • For correspondence: koujim@rs.tus.ac.jp
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Abstract

Background The expansion of intratumoral stem-like CD8+ T (Tstem) cells provides a potential approach to improving the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, here we demonstrate a strategy to facilitate Tstem cell expansion by combining an alarmin high-mobility group nucleosome binding domain 1 (HMGN1) peptide with programmed death-ligand 1 (PD-L1) blockade.

Methods The antitumor effects of HMGN1, anti-PD-L1 antibody, and their combined treatment were monitored in the B16F10, LLC, Colon26, or the EO771 tumor-bearing mice. The comprehensive immunologic analyses, such as high-dimensional flow cytometry, transcriptome analysis, and single-cell RNA sequencing, were used to investigate the cellular and molecular mechanisms of antitumor immune responses after treatments.

Results The HMGN1 peptide synergizes with PD-L1 blockade in augmenting the number of mature DCs enriched in immunoregulatory molecules (mregDCs) in tumors, and enhancing their MHC class I antigen-presenting program, which is correlated with the expansion of intratumoral Tstem cells, specifically promoting the Tstem cells but restricting terminally exhausted CD8+ T (Tex) cells, owing to the regulatory molecules expressed on mregDCs.

Conclusion Our results indicate that HMGN1 peptide serves as an immunoadjuvant to promote effective anti-PD-L1 immunotherapy and implicate that mregDCs play a role beyond facilitating Tstem cell expansion.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Revised the Abstract and the single-cell RNA sequencing library preparation and analysis in the Method.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 25, 2021.
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Combining an alarmin HMGN1 peptide with PD-L1 blockade facilitates stem-like CD8+ T cell expansion and results in robust antitumor effects
Chang-Yu Chen, Satoshi Ueha, Yoshiro Ishiwata, Shigeyuki Shichino, Shoji Yokochi, De Yang, Joost J. Oppenheim, Haru Ogiwara, Shungo Deshimaru, Yuzuka Kanno, Tatsuro Ogawa, Shiro Shibayama, Kouji Matsushima
bioRxiv 2020.12.15.422990; doi: https://doi.org/10.1101/2020.12.15.422990
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Combining an alarmin HMGN1 peptide with PD-L1 blockade facilitates stem-like CD8+ T cell expansion and results in robust antitumor effects
Chang-Yu Chen, Satoshi Ueha, Yoshiro Ishiwata, Shigeyuki Shichino, Shoji Yokochi, De Yang, Joost J. Oppenheim, Haru Ogiwara, Shungo Deshimaru, Yuzuka Kanno, Tatsuro Ogawa, Shiro Shibayama, Kouji Matsushima
bioRxiv 2020.12.15.422990; doi: https://doi.org/10.1101/2020.12.15.422990

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