Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma.
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ABSTRACT:
SUBMITTER: van Rooij N
PROVIDER: S-EPMC3836220 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
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Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma.
van Rooij Nienke N van Buuren Marit M MM Philips Daisy D Velds Arno A Toebes Mireille M Heemskerk Bianca B van Dijk Laura J A LJ Behjati Sam S Hilkmann Henk H El Atmioui Dris D Nieuwland Marja M Stratton Michael R MR Kerkhoven Ron M RM Kesmir Can C Haanen John B JB Kvistborg Pia P Schumacher Ton N TN
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20130916 32
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Project description:BackgroundAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4+T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress.MethodsWe analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT.ResultsWe discovered that neoantigen-specific TIL clones were predominantly CD4+ T cells and were present in both therapeutic responders and non-responders. CD4+ TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4+ TIL.ConclusionsDespite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4+ T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4+ TIL in future ACT protocols as a strategy to improve antitumor immunity.
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