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Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers
Frank J Lowery1, Sri Krishna1, Rami Yossef1
1Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.
Insights
Identifying tumor-specific T cell receptors (TCRs) is crucial for cancer immunotherapy. This study reveals TCR signatures in tumor-infiltrating lymphocytes (TILs) that can predict TCR function, advancing cell-based cancer treatments.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Accurate identification of antitumor T cell receptors (TCRs) is a significant hurdle in developing effective cell-based cancer immunotherapies.
- Tumor-infiltrating lymphocytes (TILs) play a critical role in anti-tumor immunity, but their specific TCRs are challenging to pinpoint.
Purpose of the Study:
- To identify and characterize neoantigen-specific TCR clonotypes (NeoTCRs) from metastatic tumors.
- To establish predictive signatures of neoantigen-reactive TILs based on transcriptomic data.
- To assess the potential of these signatures for engineering cancer immunotherapies.
Main Methods:
- Single-cell transcriptomic analysis of 55 NeoTCRs from 10 metastatic human tumors.
- Mapping TCR clonotypes to their corresponding TIL transcriptomes to identify CD8+ and CD4+ neoantigen-reactive TILs.
- Prospective prediction and validation of NeoTCR signatures.
Main Results:
- Identified distinct transcriptomic signatures for CD8+ and CD4+ neoantigen-reactive TILs.
- Neoantigen-specific TILs showed tumor-specific expansion and dysfunctional phenotypes.
- NeoTCR signatures successfully predicted TCRs recognizing tumor antigens and autologous tumors.
- Discovered that NeoTCR signatures target driver neoantigens and other tumor antigens, indicating a common TIL exhaustion program.
Conclusions:
- NeoTCR signatures provide a comprehensive map of TILs in metastatic tumors.
- Transcriptomic states of TILs can enable accurate TCR prediction for cancer immunotherapy.
- This approach facilitates the engineering of cell-based therapies by identifying functional TCRs.
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