Targeting human melanoma neoantigens by T cell receptor gene therapy
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.
Insights
T-cell responses targeting cancer neoantigens are crucial for immunotherapy. This study shows that not all neoantigens are equally effective targets for T-cell receptor (TCR) gene therapy, impacting treatment efficacy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Successful cancer immunotherapy relies on T cell responses against neoantigens from somatic mutations.
- Direct evidence linking neoantigen-specific T cells to established cancer regression is limited.
- Cyclin-dependent kinase 4 (CDK4) mutations are found in human melanoma.
Purpose of the Study:
- To investigate the efficacy of targeting specific CDK4 neoantigens using T-cell receptor (TCR) gene therapy.
- To determine if neoantigen quality influences T cell-mediated tumor rejection in vivo.
- To establish a predictive model for neoantigen immunogenicity in cancer immunotherapy.
Main Methods:
- Generated T cells with mutation-specific transgenic TCRs targeting CDK4 mutations (R24C, R24L).
- Utilized a syngeneic HLA-A2-transgenic mouse model with established tumors.
- Validated the in vivo model using a known melan-A-specific TCR (DMF5).
Main Results:
- TCR-modified T cells targeting the R24L neoantigen showed efficient expansion and IFN-γ production in vivo.
- TCR-modified T cells targeting the R24C neoantigen failed to induce significant antitumor responses.
- The model demonstrated that neoantigen presentation (analog vs. native MART-1) impacts tumor rejection efficacy.
Conclusions:
- Neoantigen quality significantly affects the therapeutic efficacy of TCR gene therapy.
- Differences in neoantigen immunogenicity may explain variable patient responses to cancer immunotherapy.
- The developed model can identify effective neoantigen targets and predict clinical outcomes for TCR-based therapies.
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