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Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses

View ORCID ProfileHiroyasu Aoki, Mikiya Tsunoda, Haru Ogiwara, Haruka Shimizu, Haruka Abe, View ORCID ProfileTakaya Abe, View ORCID ProfileShigeyuki Shichino, Kouji Matsushima, View ORCID ProfileSatoshi Ueha
doi: https://doi.org/10.1101/2022.04.19.488731
Hiroyasu Aoki
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda city, Chiba, 278-8510, Japan
2Department of Hygiene; Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
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Mikiya Tsunoda
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda city, Chiba, 278-8510, Japan
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Haru Ogiwara
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda city, Chiba, 278-8510, Japan
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Haruka Shimizu
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda city, Chiba, 278-8510, Japan
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Haruka Abe
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda city, Chiba, 278-8510, Japan
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Takaya Abe
3Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Chuo-ku, Kobe, Hyogo, 650-0047, 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, Noda city, Chiba, 278-8510, 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, Noda city, Chiba, 278-8510, Japan
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Satoshi Ueha
1Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda city, Chiba, 278-8510, Japan
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  • For correspondence: ueha@rs.tus.ac.jp
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Abstract

The repertoire of tumor-infiltrating T cells is an emerging perspective for characterizing effective antitumor T-cell responses. Oligoclonal expansion of tumor T-cell repertoire has been evaluated; however, their association with antitumor effects is unclear. We demonstrated that the polyclonal fraction of the tumor-reactive T-cell repertoire consisting of relatively minor clones increased in tumor-bearing mice treated with anti-PD-L1 or anti-CD4 monoclonal antibody, which was correlated with antitumor effect. Meanwhile, the size of the oligoclonal fraction consisting of major clones remained unchanged. Moreover, the polyclonal fraction was enriched in progenitor exhausted T cells, which are essential for a durable antitumor response, and was more dependent on CCR7+ migratory dendritic cells, which are responsible for priming tumor-reactive T cells in the tumor-draining lymph nodes. These results suggest that the expansion of diverse tumor-reactive clones (“clonal spreading”) is an important mechanism by which anti-PD-L1 and anti-CD4 treatments induce robust and durable antitumor T-cell responses.

Competing Interest Statement

H.A. reports stock for ImmunoGeneTeqs, Inc. S.U. reports advisory role for ImmunoGeneTeqs, Inc; stock for ImmunoGeneTeqs, Inc, IDAC Theranostics, Inc. S.S. reports advisory role for ImmunoGeneTeqs, Inc; stock for ImmunoGeneTeqs, Inc, K.M. reports consulting or advisory role for Kyowa-Hakko Kirin, ImmunoGeneTeqs, Inc; research funding from Kyowa-Hakko Kirin, and Ono; stock for ImmunoGeneTeqs, Inc, IDAC Theranostics, Inc.

Footnotes

  • We revised Figure 3 (e-g) and Supplementary Figure 2 (e,f) because we found bags in our data analysis pipeline. We also added the Supplementary Tables that describe information about reagents.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 23, 2022.
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Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses
Hiroyasu Aoki, Mikiya Tsunoda, Haru Ogiwara, Haruka Shimizu, Haruka Abe, Takaya Abe, Shigeyuki Shichino, Kouji Matsushima, Satoshi Ueha
bioRxiv 2022.04.19.488731; doi: https://doi.org/10.1101/2022.04.19.488731
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Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses
Hiroyasu Aoki, Mikiya Tsunoda, Haru Ogiwara, Haruka Shimizu, Haruka Abe, Takaya Abe, Shigeyuki Shichino, Kouji Matsushima, Satoshi Ueha
bioRxiv 2022.04.19.488731; doi: https://doi.org/10.1101/2022.04.19.488731

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