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The conventional dendritic cell 1 subset primes CD8+ T cells and traffics tumor antigen to drive anti-tumor immunity in the brain

View ORCID ProfileJay A. Bowman-Kirigin, Brian T. Saunders, Rupen Desai, Anthony Z. Wang, Max O. Schaettler, Connor J. Liu, Alexandra J. Livingstone, Dale K. Kobayashi, Vivek Durai, Nicole M. Kretzer, Gregory J. Zipfel, Eric C. Leuthardt, Joshua W. Osbun, Michael R. Chicoine, Albert H. Kim, Kenneth M. Murphy, Tanner M. Johanns, Bernd H. Zinselmeyer, Gavin P. Dunn
doi: https://doi.org/10.1101/2021.09.13.460088
Jay A. Bowman-Kirigin
1Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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  • ORCID record for Jay A. Bowman-Kirigin
Brian T. Saunders
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Rupen Desai
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Anthony Z. Wang
1Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Max O. Schaettler
1Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Connor J. Liu
1Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Alexandra J. Livingstone
5Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Dale K. Kobayashi
1Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Vivek Durai
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Nicole M. Kretzer
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Gregory J. Zipfel
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Eric C. Leuthardt
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Joshua W. Osbun
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Michael R. Chicoine
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Albert H. Kim
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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Kenneth M. Murphy
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Tanner M. Johanns
5Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Bernd H. Zinselmeyer
3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Gavin P. Dunn
1Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
2Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
4Brain Tumor Center/Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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  • For correspondence: gpdunn@wustl.edu
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Abstract

The central nervous system (CNS) antigen presenting cell (APC) which primes anti-tumor CD8+ T cell responses remains undefined. Elsewhere, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain cDC1 are rare; cDC localize to choroid plexus and dura. Using preclinical glioblastoma models and cDC1-deficient mice, we explored the role of cDC1 in CNS anti-tumor immunity. We determined that cDC1 mediate checkpoint blockade-induced survival benefit and prime neoantigen-specific CD8+ T cells against brain tumors. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor-antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1-equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same subsets, we identified a tumor-specific fluorescent metabolite of 5- aminolevulinic acid, which labels tumor cells during fluorescence-guided glioblastoma resection. Together, these data elucidate the specialized behavior of cDC1 and suggest cDC1 play a significant role in CNS anti-tumor immunity.

One Sentence Summary CNS cDC1 engage in previously undefined behavior to establish immune responses against brain tumors.

Competing Interest Statement

GPD is a member of the Scientific Advisory Board of Ziopharm Oncology, the clinical advisory board of ImmunoGenesis, and is a co-founder of Immunovalent. AHK has received research grants from Monteris Medical for a mouse laser therapy study as well as from Stryker and Collagen Matrix for clinical outcomes studies about a dural substitute, which have no direct relation to this study. All other authors declare they have no competing interests.

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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The conventional dendritic cell 1 subset primes CD8+ T cells and traffics tumor antigen to drive anti-tumor immunity in the brain
Jay A. Bowman-Kirigin, Brian T. Saunders, Rupen Desai, Anthony Z. Wang, Max O. Schaettler, Connor J. Liu, Alexandra J. Livingstone, Dale K. Kobayashi, Vivek Durai, Nicole M. Kretzer, Gregory J. Zipfel, Eric C. Leuthardt, Joshua W. Osbun, Michael R. Chicoine, Albert H. Kim, Kenneth M. Murphy, Tanner M. Johanns, Bernd H. Zinselmeyer, Gavin P. Dunn
bioRxiv 2021.09.13.460088; doi: https://doi.org/10.1101/2021.09.13.460088
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The conventional dendritic cell 1 subset primes CD8+ T cells and traffics tumor antigen to drive anti-tumor immunity in the brain
Jay A. Bowman-Kirigin, Brian T. Saunders, Rupen Desai, Anthony Z. Wang, Max O. Schaettler, Connor J. Liu, Alexandra J. Livingstone, Dale K. Kobayashi, Vivek Durai, Nicole M. Kretzer, Gregory J. Zipfel, Eric C. Leuthardt, Joshua W. Osbun, Michael R. Chicoine, Albert H. Kim, Kenneth M. Murphy, Tanner M. Johanns, Bernd H. Zinselmeyer, Gavin P. Dunn
bioRxiv 2021.09.13.460088; doi: https://doi.org/10.1101/2021.09.13.460088

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