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Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

Nature Medicine volume 24, pages 986–993 (2018)Cite this article

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Abstract

The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes1. Although T cells are the predominant TIL population2, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8+ TRM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.

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Fig. 1: TILs in primary versus metastatic breast cancer, and CD8 populations expressing CD103.
Fig. 2: Single-cell RNA-seq of 6,311 purified CD3+ single T cells from human primary TNBCs.
Fig. 3: Characterization of CD8+CD103+ T cells using flow cytometry, bulk RNA-seq, functional studies and TCR repertoire.
Fig. 4: Superior prognostic abilities of the TRM CD8+ gene signature derived from single-cell data in human early-stage TNBCs.

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  • 22 August 2018

    In the version of this article originally published, the institution in affiliation 10 was missing. Affiliation 10 was originally listed as Department of Surgery, Royal Melbourne Hospital and Royal Womens’ Hospital, Melbourne, Victoria, Australia. It should have been Department of Surgery, Royal Melbourne Hospital and Royal Womens’ Hospital, University of Melbourne, Melbourne, Victoria, Australia. The error has been corrected in the HTML and PDF versions of this article.

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Acknowledgements

We wish to thank H. Thorne, E. Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (which has received funding from the National Health and Medical Research Council of Australia (NHMRC), the National Breast Cancer Foundation (NBCF), Cancer Australia and the National Institute of Health (United States) for their contributions to this research, and the many families who contribute to kConFab. We wish to thank the FACS core facility staff R. Rossi, V. Milovac and S. Curcio, and T. Tan and P. Petrone for additional FACS assistance. We also thank S. Ellis for assistance with confocal imaging, G. M. Arnau for facilitating RNA-seq, and the Anatomical Pathology staff at the Peter MacCallum Cancer Centre. Special thanks also to J. Jabbari and the Australian Genome Research Facility for making the single-cell sequencing possible.

This study was funded by the Breast Cancer Research Foundation (BCRF), NY. S.L. is supported by the Cancer Council Victoria John Colebatch Fellowship and the National Breast Cancer Foundation. P.S. is supported by the NHMRC and the NBCF (Post Graduate Scholarship 1094388), the Cancer Therapeutics CRC and the Peter Mac Foundation. Z.L.T. is supported by the NHMRC (Early Career Fellowship 1106967). D.G. is supported by the Peter Mac Foundation. P.A.B. is supported by the NHMRC (Early Career Fellowship 17-005). S.J.L is supported by the University of Melbourne. S.B.F. is supported by the NHMRC (Practitioner Fellowship 1079329). kConFab is supported by a grant from NBCF, and previously NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. P.K.D is supported by the NHMRC (Senior Research Fellowship 1136680 and Program Grant 1132373). T.S. is supported by the NHMRC (Program Grant 1054618). P.J.N. is supported by the NHMRC (Program Grant 1132373).

Author information

Author notes

  1. These authors contributed equally: Peter Savas, Balaji Virassamy.

  2. These authors jointly directed this work: Laura K. Mackay, Paul J. Neeson, Sherene Loi.

  3. A full list of members and affiliations appears in the Supplementary Note.

Authors and Affiliations

  1. Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia

    Peter Savas, Balaji Virassamy, Christopher P. Mintoff, Franco Caramia, Roberto Salgado, Zhi L. Teo, Sathana Dushyanthen, Ann Byrne, Lironne Wein, Stephen J. Luen, Paul A. Beavis, Phillip K. Darcy, Paul J. Neeson & Sherene Loi

  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Peter Savas, Zhi L. Teo, Paul A. Beavis, Stephen B. Fox, Phillip K. Darcy, Paul J. Neeson & Sherene Loi

  3. Bioinformatics Division, Walter & Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

    Chengzhong Ye, Agus Salim & Terence P. Speed

  4. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

    Chengzhong Ye

  5. School of Medicine, Tsinghua University, Beijing, China

    Chengzhong Ye

  6. Department of Mathematics and Statistics, La Trobe University, Melbourne, Victoria, Australia

    Agus Salim

  7. Department of Pathology, GZA Ziekenhuizen, Antwerp, Belgium

    Roberto Salgado

  8. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    David J. Byrne & Stephen B. Fox

  9. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Catherine Poliness, Sophie S. Nightingale, Anita S. Skandarajah, David E. Gyorki & Chantel M. Thornton

  10. Department of Surgery Royal Melbourne Hospital and Royal Womens’ Hospital, University of Melbourne, Melbourne, Victoria, Australia

    Anita S. Skandarajah

  11. Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia

    Terence P. Speed

  12. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

    Laura K. Mackay

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Consortia

Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

Contributions

P.S. conceived and designed the study, provided and collected study materials and samples and patient data, performed experiments, analyzed data and wrote the manuscript. B.V. designed the study, provided and collected study materials and samples and patient data, performed experiments, analyzed data and wrote the manuscript. C.Y. developed analysis methods and software, analyzed data and wrote the manuscript. A.S. developed analysis methods and software, analyzed single-cell sequencing data and wrote the manuscript. C.P.M performed experiments, analyzed data and wrote the manuscript. F.C. analyzed data and wrote the manuscript. R.S. analyzed data and wrote the manuscript. D.J.B performed experiments and wrote the manuscript. Z.L.T. provided and collected study materials and samples, analyzed data and wrote the manuscript. S.D. performed experiments, analyzed data and wrote the manuscript. A.B. performed experiments, analyzed data and wrote the manuscript. L.W. provided and collected study materials and samples and patient data and wrote the manuscript. S.J.L. provided and collected study materials and samples and patient data and wrote the manuscript. C.P. provided and collected study materials and samples and patient data. S.S.N. provided and collected study materials and samples and patient data. A.S.S. provided and collected study materials and samples and patient data. D.E.G. provided and collected study materials and samples and patient data. C.M.T. provided and collected study materials and samples and patient data. P.A.B. analyzed data and wrote the manuscript. S.B.F provided and collected study materials and samples and patient data, analyzed data and wrote the manuscript. kConFab provided and collected study materials and samples. P.K.D. designed the study, analyzed data and wrote the manuscript. T.P.S. developed analysis methods and software, designed the study and wrote the manuscript. L.K.M. designed the study and wrote the manuscript. P.J.N. designed the study and wrote the manuscript. S.L. conceived and designed the study, provided and collected study materials and samples and patient data and wrote the manuscript.

Corresponding authors

Correspondence to Paul J. Neeson or Sherene Loi.

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Supplementary information

Supplementary Text and and Table

Supplementary Figures 1–15 and Supplementary Table 1

Reporting Summary

Supplementary Table 2

CD8 TRM signatures derived from single-cell sequencing.

Supplementary Table 3

Differential expression between all clusters in single-cell sequencing.

Supplementary Table 4

Differential expression between flow sorted CD8+CD69+CD103+ and CD8+CD69+CD103 T cells from 2 primary breast (TNBC and HER2) cancers and 1 liver metastasis (TNBC) from 3 different patients.

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Savas, P., Virassamy, B., Ye, C. et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med 24, 986–993 (2018). https://doi.org/10.1038/s41591-018-0078-7

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