Capturing and Tracking Clonal T-cell Response to Cancer Neoantigens.

Area of Science:

• Immunology
• Oncology
• Bioinformatics

Background:

• T cell receptor (TCR) specificity is crucial for understanding immune responses.
• Limited knowledge of TCR repertoire specificities hinders diagnostic and preclinical research.
• Antigen-specific T cell responses are key to effective cancer immunotherapy.

Purpose of the Study:

• To develop and validate a cost-efficient pipeline for identifying mouse TCR specificities.
• To create a dataset of helper T cell (Th) TCRβ CDR3s specific to B16 melanoma neoantigens.
• To track tumor-specific T cell responses to CTLA4 blocking immunotherapy in a B16 melanoma model.

Main Methods:

• Developed a wet lab and computational pipeline for TCR specificity identification.
• Generated a dataset of TCRβ CDR3 sequences specific to B16 melanoma neoantigens.
• Applied the dataset to analyze T cell responses in an orthotopic B16 melanoma mouse model treated with CTLA4 blockade.

Main Results:

• Identified expansion of B16-specific TCR motifs in both Th and regulatory T cell (Treg) repertoires.
• Observed stronger TCR motif expansion in the Th subset of CTLA4-treated mice.
• Demonstrated stochastic, mouse-specific T cell response patterns and CTLA4 blockade-induced Th-to-Treg plasticity.

Conclusions:

• The developed pipeline enables antigen-specific investigation of mouse T cell responses.
• CTLA4 blockade promotes Th clonal expansion and Th-to-Treg plasticity.
• The findings facilitate the development and validation of immunotherapies and vaccination strategies.