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Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

Kristen E. Pauken, Osmaan Shahid, Kaitlyn A. Lagattuta, Kelly M. Mahuron, Jacob M. Luber, Margaret M. Lowe, Linglin Huang, Conor Delaney, Jaclyn M. Long, Megan E. Fung, Kathleen Newcomer, Katy K. Tsai, Melissa Chow, Samantha Guinn, Juhi R. Kuchroo, Kelly P. Burke, Jason M. Schenkel, View ORCID ProfileMichael D. Rosenblum, View ORCID ProfileAdil I. Daud, View ORCID ProfileArlene H. Sharpe, View ORCID ProfileMeromit Singer
doi: https://doi.org/10.1101/2020.09.30.294959
Kristen E. Pauken
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
2Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
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Osmaan Shahid
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
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Kaitlyn A. Lagattuta
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
4Harvard-MIT Medical Scientist Training Program, Harvard Medical School, Boston, MA, USA
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Kelly M. Mahuron
5Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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Jacob M. Luber
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
7Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
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Margaret M. Lowe
8Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
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Linglin Huang
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
9Department of Biostatistics, Harvard H. Chan School of Public Health, Boston, MA, USA
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Conor Delaney
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
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Jaclyn M. Long
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
2Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
10Department of Bioengineering, Northeastern University, Boston, MA, USA
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Megan E. Fung
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
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Kathleen Newcomer
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
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Katy K. Tsai
11Department of Medicine, University of California San Francisco, San Francisco, CA, USA
12Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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Melissa Chow
12Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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Samantha Guinn
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
2Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
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Juhi R. Kuchroo
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
2Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
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Kelly P. Burke
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
2Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
13Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
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Jason M. Schenkel
14Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
15Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
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Michael D. Rosenblum
8Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
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  • ORCID record for Michael D. Rosenblum
  • For correspondence: Michael.Rosenblum@ucsf.edu Adil.Daud@ucsf.edu arlene_sharpe@hms.harvard.edu msinger@ds.dfci.harvard.edu
Adil I. Daud
11Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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  • For correspondence: Michael.Rosenblum@ucsf.edu Adil.Daud@ucsf.edu arlene_sharpe@hms.harvard.edu msinger@ds.dfci.harvard.edu
Arlene H. Sharpe
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
2Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Arlene H. Sharpe
  • For correspondence: Michael.Rosenblum@ucsf.edu Adil.Daud@ucsf.edu arlene_sharpe@hms.harvard.edu msinger@ds.dfci.harvard.edu
Meromit Singer
1Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
3Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
6Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Meromit Singer
  • For correspondence: Michael.Rosenblum@ucsf.edu Adil.Daud@ucsf.edu arlene_sharpe@hms.harvard.edu msinger@ds.dfci.harvard.edu
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Abstract

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize “tumor matching” (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.

Summary Using single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood.

Competing Interest Statement

The authors declare the enclosed potential conflicts of interest. M.D.R. is a founder of TRex Bio and Sitryx Bio and receives research funding from Abbvie, LEO Pharma, and TRex bio. A.I.D. has funds from Merck, Oncosec, BMS, Roche, Genentech, Pfizer, Incyte, Novartis and Checkmate, is on advisory boards for Xencor, Pfizer, Array, has stock in TRex, SQZ bio., and patents with Oncosec on Gene Therapy of melanoma. A.H.S. has patents on the PD-1 pathway licensed by Roche/Genentech and Novartis, consults for Novartis, is on the scientific advisory boards for Surface Oncology, Sqz Biotech, Elstar Therapeutics, Elpiscience, Selecta and Monopteros, and has research funding from Merck, Novartis, Roche, and Quark Ventures. K.K.T discloses institutional research funding from Array/Pfizer, BMS, Oncosec, Regeneron, and Replimune. From August 4th 2020, MS is an employee of Guardant Health. The authors have no additional financial conflicts of interest to disclose.

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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. It is made available under a CC-BY-NC 4.0 International license.
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Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment
Kristen E. Pauken, Osmaan Shahid, Kaitlyn A. Lagattuta, Kelly M. Mahuron, Jacob M. Luber, Margaret M. Lowe, Linglin Huang, Conor Delaney, Jaclyn M. Long, Megan E. Fung, Kathleen Newcomer, Katy K. Tsai, Melissa Chow, Samantha Guinn, Juhi R. Kuchroo, Kelly P. Burke, Jason M. Schenkel, Michael D. Rosenblum, Adil I. Daud, Arlene H. Sharpe, Meromit Singer
bioRxiv 2020.09.30.294959; doi: https://doi.org/10.1101/2020.09.30.294959
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Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment
Kristen E. Pauken, Osmaan Shahid, Kaitlyn A. Lagattuta, Kelly M. Mahuron, Jacob M. Luber, Margaret M. Lowe, Linglin Huang, Conor Delaney, Jaclyn M. Long, Megan E. Fung, Kathleen Newcomer, Katy K. Tsai, Melissa Chow, Samantha Guinn, Juhi R. Kuchroo, Kelly P. Burke, Jason M. Schenkel, Michael D. Rosenblum, Adil I. Daud, Arlene H. Sharpe, Meromit Singer
bioRxiv 2020.09.30.294959; doi: https://doi.org/10.1101/2020.09.30.294959

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