Neoantigen landscape dynamics during human melanoma–T cell interactions
Menée sur deux patients atteints d'un mélanome de stade IV traité à l'aide d'un transfert adoptif de lymphocytes T, cette étude met en évidence la dynamique des interactions entre les cellules cancéreuses et les lymphocytes T
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. Therefore, strategies to selectively enhance T cell reactivity against genetically defined neoantigens 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. 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 stage IV melanoma patients treated by adoptive T cell transfer. The T-cell-recognized neoantigens can selectively be lost from the tumour cell population, either by overall reduced expression of the gene or loss of the mutant allele. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of a novel neoantigen-specific T cell reactivity within tumour-infiltrating lymphocytes. These data demonstrate the dynamic nature of cancer–T cell interactions, suggestive of T-cell-mediated neoantigen immunoediting, and argue for the therapeutic induction of broad neoantigen-specific T cell responses to avoid tumour resistance.