Abstract

Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint blockade and adoptive T-cell therapy1,2,3,4,5,6,7. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens1,8,9,10,11 are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens12,13. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance.

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Acknowledgements

We are grateful to G. J. Liefers for handling of patient material, and T. van Wezel and D. Ruano for the setup of the M13-amplicon sequencing technology. This work was supported by Dutch Cancer Society grant UL 2012-5544 (to E.M.E.V., S.H.v.d.B. and J.B.A.G.H), the Anticancer Fund (to E.M.E.V. and S.H.v.d.B.), Dutch Cancer Society grant NKI 2012-5463 (to T.N.S, J.B.A.G.H. and S.H.v.d.B), the Dutch Cancer Society Queen Wilhelmina Award NKI 2013-6122 (T.N.S), Dutch Cancer Society grant UVA 2010-4822 (to H.S.), Fight Colorectal Cancer-Michael’s Mission-AACR Fellowship (2015) and Alpe d’HuZes/KWF Bas Mulder Award (to N.F.C.C.d.M.).

Author information

Author notes

    • Marit M. van Buuren
    • , Rikke S. Andersen
    •  & Sine R. Hadrup

    Present addresses: Neon Therapeutics, Cambridge, Massachusetts 02142, USA (M.M.v.B.); Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark (R.S.A.); Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1870 Frederiksberg, Copenhagen, Denmark (S.R.H.).

Affiliations

  1. Department of Medical Oncology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

    • Els M. E. Verdegaal
    • , Marten Visser
    • , Tom Harryvan
    • , Caroline E. van der Minne
    • , John B. A. G. Haanen
    • , Ellen H. W. Kapiteijn
    •  & Sjoerd H. van der Burg
  2. Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

    • Noel F. C. C. de Miranda
  3. Department of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

    • Marit M. van Buuren
    • , John B. A. G. Haanen
    •  & Ton N. Schumacher
  4. Department of Hematology, Center for Cancer Immune Therapy, University Hospital Herlev, 2730 Herlev, Denmark

    • Rikke S. Andersen
    •  & Sine R. Hadrup
  5. AIMM Therapeutics, 1105 BA Amsterdam, The Netherlands

    • Remko Schotte
    •  & Hergen Spits
  6. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

    • Hergen Spits

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Contributions

E.M.E.V. designed, performed, analysed and interpreted experiments and wrote the paper, N.F.C.C.d.M., M.V., C.E.v.d.M. and T.H. designed, performed, analysed and interpreted the experiments, M.M.v.B. analysed and interpreted next-generation sequencing data and performed peptide selection, R.S.A. and S.R.H. designed, performed and interpreted the combinatorial coding experiments, R.S. generated BCL-6/BCL-XL immortalized B-cell lines. E.H.W.K and J.B.A.G.H. supervised treatment of patients, supplied patient material and provided clinical interpretation of results. H.S. developed the BCL-6/BCL-XL immortalization technology. T.N.S. interpreted the data and wrote the paper, S.H.v.d.B. supervised the project, designed and interpreted the experiments, and wrote the paper.

Competing interests

AIMM Therapeutics holds IP to immortalize human B cells, and AIMM Therapeutics/ The Netherlands Cancer Institute hold IP for the use of immortalized human B cells to identify T cell epitopes. H.S. and R.S. are employees and stockholders of AIMM Therapeutics. T.N.S. is a scientific advisor and stockholder of AIMM Therapeutics.

Corresponding author

Correspondence to Els M. E. Verdegaal.

Reviewer Information

Nature thanks M. Gubin, U. Sahin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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DOI

https://doi.org/10.1038/nature18945

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