TY - JOUR
T1 - Neoantigen landscape dynamics during human melanoma-T cell interactions
AU - Verdegaal, Els M. E.
AU - de Miranda, Noel F. C. C.
AU - Visser, Marten
AU - Harryvan, Tom
AU - van Buuren, Marit M.
AU - Andersen, Rikke S.
AU - Hadrup, Sine R.
AU - van der Minne, Caroline E.
AU - Schotte, Remko
AU - Spits, Hergen
AU - Haanen, John B. A. G.
AU - Kapiteijn, Ellen H. W.
AU - Schumacher, Ton N.
AU - van der Burg, Sjoerd H.
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - https://doi.org/10.1038/nature18945
DO - https://doi.org/10.1038/nature18945
M3 - Article
C2 - 27350335
SN - 0028-0836
VL - 536
SP - 91-+
JO - NATURE
JF - NATURE
IS - 7614
ER -