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Natural high-avidity T-cell receptor efficiently mediates regression of cancer/testis antigen 83 positive common
Qingyang Li1, Wei Hu2, Baoyi Liao1
1Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China.
Background:
T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging success in anticancer clinical trials. The antigenic targets, however, were primarily focused on human leukocyte antigen (HLA) A*02:01 restricted epitopes from a few cancer/testis antigens (CTAs) which are not widely expressed in common solid cancers; the tested T-cell receptors (TCRs) were frequently from tumor-infiltrating lymphocytes of old patients and were not assured to have higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs that are frequently expressed in common solid cancers.
Methods:
We selected the CT83 protein, which is frequently expressed in common solid cancers, as a model antigen for screening of its specific TCR. The predicted CT83 epitopes with strong or weak binding to HLA-I molecules, popular in the Chinese population, were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the CD137 biomarker for single-cell sequencing to obtain the paired TCRαβ sequence. The higher frequency TCRs were reconstructed for characterization of the CT83 epitope and for assessment of in vitro and in vivo antitumor activities.
Results:
CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated stimulation with DCs and peptides. The single-cell TCR sequencing results of reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. T cells engineered with this dominant TCR led to HLA-A*11:01-restricted recognition of the CT8314-22 epitope, with higher avidity. Functional assays showed powerful cytotoxicity in vitro against the targets of several CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic efficacy in three xenograft solid tumor models. The meta-analysis of gene expression of 92 CTAs indicated that most CTAs did not or at low levels in the thymus, which suggested that those CTAs may experience incomplete thymic central tolerance.
Conclusions:
High-avidity TCR against CT83 could be isolated from YHDs and efficiently mediate regression of well-established xenograft common solid tumors. The high-avidity TCR repertoire in the peripheral blood of some donors for CT83 and other CTAs provides the basis for the efficient isolation of high-avidity TCRs to target numerous solid cancers.
Insights
Researchers isolated high-avidity T-cell receptors (TCRs) targeting CT83, a common cancer antigen. Engineered T cells demonstrated potent anti-tumor activity in vitro and in vivo, offering a promising strategy for solid cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- T-cell receptor-engineered T cells (TCR-Ts) show promise in cancer therapy.
- Current TCR-T therapies target limited cancer/testis antigens (CTAs) with restricted HLA types and variable T-cell avidity.
- There is a need for high-avidity TCRs targeting broadly expressed CTAs in solid tumors.
Purpose of the Study:
- To isolate high-avidity TCRs against frequently expressed cancer antigens in common solid cancers.
- To characterize and evaluate the anti-tumor efficacy of these novel TCRs.
Main Methods:
- Selected CT83 protein as a model antigen, frequently expressed in solid cancers.
- Generated CT83-specific CD8+ T cells from young healthy donors using peptide-loaded dendritic cells (DCs).
- Employed single-cell sequencing to identify dominant TCR clonotypes and engineered T cells for functional and in vivo efficacy assessment.
Main Results:
- Identified a dominant TCR clonotype enabling HLA-A*11:01-restricted recognition of the CT8314-22 epitope with high avidity.
- Engineered TCR-T cells exhibited potent in vitro cytotoxicity against CT83-positive solid cancer cell lines.
- Demonstrated significant therapeutic efficacy in three xenograft solid tumor models.
Conclusions:
- High-avidity TCRs against CT83 can be effectively isolated from young healthy donors.
- These TCR-Ts mediate regression of established solid tumors, highlighting their therapeutic potential.
- The identified TCR repertoire provides a basis for targeting numerous solid cancers with improved avidity.
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