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Targeting human melanoma neoantigens by T cell receptor gene therapy

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Item Type:Article
Title:Targeting human melanoma neoantigens by T cell receptor gene therapy
Creators Name:Leisegang, M. and Kammertoens, T. and Uckert, W. and Blankenstein, T.
Abstract:In successful cancer immunotherapy, T cell responses appear to be directed toward neoantigens created by somatic mutations; however, direct evidence that neoantigen-specific T cells cause regression of established cancer is lacking. Here, we generated T cells expressing a mutation-specific transgenic T cell receptor (TCR) to target different immunogenic mutations in cyclin-dependent kinase 4 (CDK4) that naturally occur in human melanoma. Two mutant CDK4 isoforms (R24C, R24L) similarly stimulated T cell responses in vitro and were analyzed as therapeutic targets for TCR gene therapy. In a syngeneic HLA-A2-transgenic mouse model of large established tumors, we found that both mutations differed dramatically as targets for TCR-modified T cells in vivo. While T cells expanded efficiently and produced IFN-γ in response to R24L, R24C failed to induce an effective antitumor response. Such differences in neoantigen quality might explain why cancer immunotherapy induces tumor regression in some individuals, while others do not respond, despite similar mutational load. We confirmed the validity of the in vivo model by showing that the melan-A-specific (MART-1-specific) TCR DMF5 induces rejection of tumors expressing analog, but not native, MART-1 epitopes. The described model allows identification of those neoantigens in human cancer that serve as suitable T cell targets and may help to predict clinical efficacy.
Keywords:Amino Acid Sequence, Antigen T-Cell Receptors, Base Sequence, Cyclin-Dependent Kinase 4, DNA Mutational Analysis, Genetic Therapy, HLA-A2 Antigen, MART-1 Antigen, Melanoma, Protein Binding, Transgenic Mice, Tumor Cell Line, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:854-858
Date:1 March 2016
Official Publication:https://doi.org/10.1172/JCI83465
PubMed:View item in PubMed

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