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Neoantigen landscape dynamics during human melanoma–T cell interactions

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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Figure 1: Identification and dynamics of neoepitope-specific T-cell reactivity and neoepitope expression in patient BO.
Figure 2: Identification and dynamics of the dominating intratumoral neoantigen-specific T-cell repertoire in patient AB.
Figure 3: Mutation analysis and neoantigen expression in sequential tumour lines and tumour tissue of patient AB.

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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.).

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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.

Corresponding author

Correspondence to Els M. E. Verdegaal.

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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.

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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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Verdegaal, E., de Miranda, N., Visser, M. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536, 91–95 (2016). https://doi.org/10.1038/nature18945

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