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A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade

Nature Medicine volume 24, pages 994–1004 (2018)Cite this article

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Abstract

Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1–) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1– lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.

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Fig. 1: Co-receptor expression, functionality and tumor reactivity of CD8+ PD-1+ TIL populations in NSCLC.
Fig. 2: Gene expression profile of sorted PD-1T, PD-1N and PD-1– TILs from NSCLC specimens.
Fig. 3: PD-1T TILs show overexpression of inhibitory receptors, but display a key gene signature distinct from exhausted T cells in murine chronic infection and cancer.
Fig. 4: Alterations in glucose, lipid and mitochondrial metabolism in PD-1T TILs.
Fig. 5: PD-1T TILs display a fixed state of dysfunction.
Fig. 6: CXCL13 expression of PD-1T TILs and predictive potential for response to PD-1 blockade.

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Acknowledgements

We thank D. Labes and E. Traunecker for exemplary technical assistance with cell sorting, F. Franco and T. Chao for performing electron microscopy analysis, L. Tietze (Ortenau Klinikum, Germany) for contribution of tumor samples, B. Dolder-Schlienger for technical assistance, and F. Uhlenbrock and D. Pinschewer for discussions and critical reading of the manuscript. This work was supported by grants from the Swiss National Science Foundation (P300PB_164755 to D.S.T., 320030_162575 to A.Z. and 31003A_163204 to P.C.H.), the Research Funds University of Basel (D.S.T.), the Lichtenstein-Stiftung (D.S.T.), the FAG-Basel (D.S.T.), the Dutch Cancer Society Queen Wilhelmina Award NKI 2013-6122 (T.N.S.) and ERC grant SENSIT (T.N.S.).

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Author notes

  1. These authors contributed equally: Viktor H. Koelzer, Petra Herzig, Andreas Roller.

  2. These authors jointly directed this work: Ton N. Schumacher, Alfred Zippelius.

Authors and Affiliations

  1. Cancer Immunology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland

    Daniela S. Thommen, Petra Herzig, Marcel Trefny & Alfred Zippelius

  2. Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Daniela S. Thommen & Ton N. Schumacher

  3. Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland

    Viktor H. Koelzer, Jonathan Hanhart & Kirsten D. Mertz

  4. Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK

    Viktor H. Koelzer

  5. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

    Andreas Roller & Anna Kiialainen

  6. Immunobiology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland

    Sarah Dimeloe & Christoph Hess

  7. Oncology, Cantonal Hospital Baselland, Liestal, Switzerland

    Catherine Schill

  8. Institute of Pathology, University Hospital Basel, Basel, Switzerland

    Spasenija Savic Prince

  9. Department of Surgery, University Hospital Basel, Basel, Switzerland

    Mark Wiese & Didier Lardinois

  10. University of Lausanne, Ludwig Center for Cancer Research, Epalinges, Switzerland

    Ping-Chih Ho

  11. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Zurich, Switzerland

    Christian Klein & Vaios Karanikas

  12. Medical Oncology, University Hospital Basel, Basel, Switzerland

    Alfred Zippelius

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Contributions

D.S.T.: study design and supervision, design and execution of the experiments; data acquisition, analysis and interpretation; writing and revision of the manuscript; V.H.K.: execution of immunohistochemistry stainings, digital image analysis; contribution to manuscript drafting and revision; P.H.: execution of experiments; contribution to manuscript drafting and revision; A.R.: statistical analysis and interpretation, contribution to manuscript drafting; M.T.: execution of experiments; A.K.: RNA-seq analysis; S.D.: design and technical support with metabolism analysis; J.H.: execution of immunohistochemistry and digital image analysis; C.S.: collection and analysis of clinical data; C.H.: design of metabolism experiments, contribution to manuscript drafting; S.S.P.: collection and pathological characterization of patient samples; M.W. and D.L.: recruitment and characterization of patients; P.C.H.: execution of experiments, contribution to manuscript drafting; C.K. and V.K.: contribution to manuscript drafting; K.D.M.: execution of immunohistochemistry analysis; contribution to manuscript drafting; T.N.S.: study design and supervision; writing and revision of the manuscript; A.Z.: study design and supervision, writing and revision of the manuscript.

Corresponding authors

Correspondence to Daniela S. Thommen or Alfred Zippelius.

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Competing interests

A.R., A.K., C.K., V.K. are employed by Roche. A.Z. received research funding from Roche. Part of the work described in this manuscript is the subject of a patent application co-owned by NKI-AVL and the University of Basel. Based on NKI-AVL and the University of Basel policy on management of intellectual property, D.S.T., V.H.K., K.D.M., A.Z. and T.N.S. would be entitled to a portion of the royalty income received.

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Supplementary information

Supplementary Figures

Supplementary Figures 1–6

Reporting Summary

Supplementary Table 1

TCR analysis data

Supplementary Table 2

Gene expression data

Supplementary Table 3

Tumor sample overview

Supplementary Table 4

Patient characteristics for predictive analysis

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Thommen, D.S., Koelzer, V.H., Herzig, P. et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med 24, 994–1004 (2018). https://doi.org/10.1038/s41591-018-0057-z

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