Journal
NATURE
Volume 536, Issue 7614, Pages 91-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature18945
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Funding
- Dutch Cancer Society [UL 2012-5544, NKI 2012-5463, UVA 2010-4822]
- Anticancer Fund
- Dutch Cancer Society Queen Wilhelmina Award NKI [2013-6122]
- Fight Colorectal Cancer-Michael's Mission-AACR Fellowship
- Alpe d'HuZes/KWF Bas Mulder Award
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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(1-7). Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens(1,8-11) 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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