Journal Article

Neoantigen landscape dynamics during human melanoma–T cell interactions

de Miranda, Noel F. C. C., Andersen, Rikke S., Haanen, John B. A. G., Kapiteijn, Ellen H. W., Schumacher, Ton N., van Buuren, Marit M., Verdegaal, Els M. E., van der Minne, Caroline E., Schotte, Remko, Spits, Hergen, van der Burg, Sjoerd H., Visser, Marten, Harryvan, Tom, Hadrup, Sine R.

2016

Overview

Analyses of tumour samples and tumour-infiltrating lymphocytes from two patients with melanoma who were treated with adoptive T-cell therapy provide evidence for tumour escape by loss and downregulation of immunogenic antigens. Tumour resistance to neoantigens A key question in the development of mutation-derived neoantigens as cancer immunotherapy is whether the neoantigen repertoire in human cancers will be stable when T-cell reactivity is elicited. Els Verdegaal et al . analyse sequential tumour samples and tumour-infiltrating lymphocytes from two patients with melanoma receiving adoptive T-cell therapy and provide evidence for tumour escape by loss and downregulation of immunogenic antigens. This result suggests that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2161 / 631/250/251 / 631/67/1813/1634 / Adoptive Transfer / Alleles / Analysis / Animals / Antigens / Antigens, Neoplasm - biosynthesis / Antigens, Neoplasm - genetics / Antigens, Neoplasm - immunology / Cancer / Cell Line, Tumor / Disease Models, Animal / DNA Damage - genetics / DNA Damage - immunology / Down-Regulation / Epitopes, T-Lymphocyte - biosynthesis / Epitopes, T-Lymphocyte - genetics / Epitopes, T-Lymphocyte - immunology / Genes / Health aspects / Humanities and Social Sciences / Humans / Immunotherapy / L Cells (Cell Line) / letter / Lymphocytes / Lymphocytes, Tumor-Infiltrating - immunology / Melanoma / Melanoma - genetics / Melanoma - immunology / Melanoma - pathology / Melanoma - therapy / Mice / multidisciplinary / Mutation / Patients / Rodents / Science / T cell receptors / T cells / T-Lymphocytes - cytology / T-Lymphocytes - immunology / Tumor antigens / Tumor Escape - immunology / Tumors