Neoantigen landscape dynamics during human melanoma-T cell interactions.
Verdegaal, Els M. E.; de Miranda, Noel F. C. C.; Visser, Marten; Harryvan, Tom; van Buuren, Marit M.; Andersen, Rikke S.; Hadrup, Sine R.; van der Minne, Caroline E.; Schotte, Remko; Spits, Hergen; Haanen, John B. A. G.; Kapiteijn, Ellen H. W.; Schumacher, Ton N.; van der Burg, Sjoerd H.
[Letter] Nature. 536(7614):91-95, August 4, 2016.

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: 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 therapy 1,2,3,4,5,6,7. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens 1,8,9,10,11 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 antigens 12,13. 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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