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A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

Kelli A. Connolly, Manik Kuchroo, Aarthi Venkat, Achia Khatun, Jiawei Wang, Ivana William, Noah Hornick, Brittany Fitzgerald, Martina Damo, Moujtaba Y. Kasmani, Can Cui, Eric Fagerberg, Isabel Monroy, Amanda Hutchins, Julie F Cheung, Gena G. Foster, Dylan L. Mariuzza, Hongyu Zhao, Weiguo Cui, Smita Krishnaswamy, Nikhil S. Joshi
doi: https://doi.org/10.1101/2021.01.27.428467
Kelli A. Connolly
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Manik Kuchroo
2Departments of Genetics and Computer Science, Yale University School of Medicine, New Haven, CT
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Aarthi Venkat
3Computational Biology and Bioinformatics Program, Yale University, New Haven, CT
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Achia Khatun
4Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
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Jiawei Wang
3Computational Biology and Bioinformatics Program, Yale University, New Haven, CT
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Ivana William
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Noah Hornick
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Brittany Fitzgerald
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Martina Damo
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Moujtaba Y. Kasmani
4Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
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Can Cui
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Eric Fagerberg
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Isabel Monroy
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Amanda Hutchins
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Julie F Cheung
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Gena G. Foster
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Dylan L. Mariuzza
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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Hongyu Zhao
5Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
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Weiguo Cui
4Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
6Versiti Blood Research Institute, Milwaukee, WI 53213
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Smita Krishnaswamy
2Departments of Genetics and Computer Science, Yale University School of Medicine, New Haven, CT
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Nikhil S. Joshi
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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  • For correspondence: nikhil.joshi@yale.edu
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Abstract

“Stem-like” TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+ tumor-specific CD8+ T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” to “cold”. By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSL CD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

Competing Interest Statement

The authors have declared no competing interest.

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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 January 27, 2021.
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A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response
Kelli A. Connolly, Manik Kuchroo, Aarthi Venkat, Achia Khatun, Jiawei Wang, Ivana William, Noah Hornick, Brittany Fitzgerald, Martina Damo, Moujtaba Y. Kasmani, Can Cui, Eric Fagerberg, Isabel Monroy, Amanda Hutchins, Julie F Cheung, Gena G. Foster, Dylan L. Mariuzza, Hongyu Zhao, Weiguo Cui, Smita Krishnaswamy, Nikhil S. Joshi
bioRxiv 2021.01.27.428467; doi: https://doi.org/10.1101/2021.01.27.428467
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A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response
Kelli A. Connolly, Manik Kuchroo, Aarthi Venkat, Achia Khatun, Jiawei Wang, Ivana William, Noah Hornick, Brittany Fitzgerald, Martina Damo, Moujtaba Y. Kasmani, Can Cui, Eric Fagerberg, Isabel Monroy, Amanda Hutchins, Julie F Cheung, Gena G. Foster, Dylan L. Mariuzza, Hongyu Zhao, Weiguo Cui, Smita Krishnaswamy, Nikhil S. Joshi
bioRxiv 2021.01.27.428467; doi: https://doi.org/10.1101/2021.01.27.428467

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