Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics

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Data availability

scRNA-seq and scATAC-seq data generated in this study are deposited in the National Center for Biotechnology Information Gene Expression Omnibus under accession GSE199565. Processed Seurat R objects are available here. Source data are provided with this paper.

Code availability

All analyses were done with custom R scripts and are available upon request using standard R packages. No new algorithms were developed during this study.

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Acknowledgements

We thank members of the laboratory of E.J.W. This work was supported by T32 CA009140 and a Cancer Research Institute-Mark Foundation Fellowship (to J.G.), by the Parker Institute for Cancer Immunotherapy and Stand Up to Cancer and National Institutes of Health (NIH) grants AI155577, AI149680, AI108545, AI082630, DK127768 and CA210944 (to E.J.W.). Work in the Wherry laboratory is supported by the Parker Institute for Cancer Immunotherapy. S.F.N. was supported by an Australia NHMRC C.J. Martin Fellowship (GNT1111469) and the Mark Foundation Momentum Fellowship. O.K. was supported by an NIAID F30 fellowship (F30AI129263). D.M. was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. J.E.W. was supported by a PICI Scholar award. Y.J.H. was supported by a National Science Foundation graduate research fellowship. A.C.H. was supported by NIH grant K08-CA230157, the Damon Runyon Clinical Investigator Award, Doris Duke Clinical Scientist Development Award, W. W. Smith Charitable Trust Award, the Tara Miller Foundation and P50 CA174523. The melanoma clinical trial was supported by SPORE grant P50CA261608.

Author information

Author notes

  1. Ryan Staupe

    Present address: Infectious Disease & Vaccines, MRL, Merck & Co. Inc., West Point, PA, USA

  2. Mohamed S. Abdel-Hakeem

    Present address: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

  3. Patrick K. Yan

    Present address: Immunology Graduate Program, Stanford University, Stanford, CA, USA

Authors and Affiliations

  1. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA

    Josephine R. Giles, Shin Foong Ngiow, Sasikanth Manne, Amy E. Baxter, Omar Khan, Ping Wang, Ryan Staupe, Mohamed S. Abdel-Hakeem, Hua Huang, Divij Mathew, Mark M. Painter, Jennifer E. Wu, Yinghui Jane Huang, Rishi R. Goel, Patrick K. Yan & E. John Wherry

  2. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Josephine R. Giles, Shin Foong Ngiow, Sasikanth Manne, Amy E. Baxter, Omar Khan, Ping Wang, Mohamed S. Abdel-Hakeem, Hua Huang, Divij Mathew, Mark M. Painter, Jennifer E. Wu, Yinghui Jane Huang, Rishi R. Goel, Alexander C. Huang & E. John Wherry

  3. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Josephine R. Giles, Shin Foong Ngiow, Jennifer E. Wu, Alexander C. Huang & E. John Wherry

  4. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA

    Ping Wang & Alexander C. Huang

  5. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA

    Hua Huang

  6. Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA

    Giorgos C. Karakousis & Xiaowei Xu

  7. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Tara C. Mitchell

  8. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Alexander C. Huang

Contributions

J.G., O.K. and E.J.W. conceived and designed the experiments. J.G., O.K. and R.S. performed FACS and prepared sequencing libraries. J.G. analyzed data with help from S.F.N., S.M. and H.H. P.W. prepared retroviruses. M.S.A. provided long-term Arm-infected mice. A.E.B., S.F.N., D.M., M.M.P., R.R.G., J.E.W. and Y.J.H. helped with experiments. For the melanoma TIL samples, A.C.H. and T.C.M. designed the trial; A.C.H., T.C.M., X.X. and G.C.K. implemented the clinical trial at Penn; T.C.M. was principal investigator of the clinical trial; and P.K.Y. performed flow cytometry on TIL samples. J.G. and E.J.W. wrote the manuscript.

Corresponding author

Correspondence to E. John Wherry.

Ethics declarations

Competing interests

E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supported the study. E.J.W. is an advisor for Danger Bio, Marengo, Janssen, Pluto Immunotherapeutics, Related Sciences, Rubius Therapeutics, Synthekine and Surface Oncology. E.J.W. is a founder of Surface Oncology, Danger Bio and Arsenal Biosciences. E.J.W. has a patent on the PD-1 pathway. O.K. holds equity in Arsenal Biosciences and is an employee of Orange Grove Bio. A.C.H. is a consultant for Immunai and receives funding from BMS. X.X. is scientific cofounder of CureBiotech and Exio Biosciences. T.M. is on the scientific advisory board for Merck, BMS, OncoSec, GigaGen and Instil Bio. G.C.K. is on the scientific advisory board for Merck and was the principal investigator of an investigator-initiated trial sponsored by Merck.

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Nature Immunology thanks Fotini Gounari and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team.

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Giles, J.R., Ngiow, S.F., Manne, S. et al. Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics. Nat Immunol (2022). https://doi.org/10.1038/s41590-022-01338-4

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  • Received: 20 March 2022

  • Accepted: 13 September 2022

  • Published: 21 October 2022

  • DOI: https://doi.org/10.1038/s41590-022-01338-4

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