Identification of T Cell Receptors Targeting a Neoantigen Derived from Recurrently Mutated FGFR3

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Immunotherapies, including immune checkpoint blockades, are crucial for cancer treatment.
• Neoantigens, arising from cancer-specific mutations, offer targeted therapy potential but are often patient-unique, posing development challenges.
• Shared neoantigens, common mutations in subsets of patients, present a promising avenue for developing broadly applicable immunotherapies.

Purpose of the Study:

• To screen for shared neoantigens and identify neoantigen-reactive T cells.
• To evaluate the functional activity of T cell receptors (TCRs) engineered to target shared neoantigens.
• To explore the potential of shared neoantigens in cancer immunotherapy strategies.

Main Methods:

• Utilized exome sequencing data from The Cancer Genome Atlas (TCGA) to predict shared neoantigen peptides.
• Performed in vitro screening of shared neoantigen-reactive CD8+ T cells from healthy donors using ELISPOT assays.
• Generated TCR-engineered T cells to assess the functional activity of neoantigen-specific TCRs.

Main Results:

• Identified the mutated FGFR3^Y373C peptide as capable of inducing antigen-specific CD8+ T cells in a donor with HLA-A*02:06.
• Isolated FGFR3^Y373C-specific CD8+ T cell clones and identified two distinct TCRs reactive to this shared neoantigen.
• Demonstrated that TCR-engineered T cells expressing these specific TCRs recognized the mutated FGFR3^Y373C peptide and exhibited cytotoxic activity against target cells.

Conclusions:

• Shared neoantigens, exemplified by FGFR3^Y373C, can elicit specific T cell responses.
• TCR-engineered T cells targeting shared neoantigens show potential for cancer treatment.
• This research supports the development of immunotherapies, such as cancer vaccines and TCR-engineered T cell therapies, targeting shared neoantigens.