Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation

Area of Science:

• Cancer immunology
• Molecular biology
• Immunotherapy

Background:

• Interferon-gamma (IFNγ) and indoleamine 2,3-dioxygenase 1 (IDO1) upregulate in cancer, causing tryptophan depletion.
• Tryptophan depletion induces ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis, creating neoepitopes.

Purpose of the Study:

• To investigate if W>F neoepitopes can serve as targets for adoptive T cell therapy.
• To identify and characterize W>F neoepitopes and their corresponding T cell receptors (TCRs).

Main Methods:

• Immunopeptidomic analysis to identify W>F neoepitopes.
• Characterization of T cell receptor (TCR) affinity and specificity.
• In vitro assessment of T cell activation by cancer cells.
• In vivo proof-of-concept studies.

Main Results:

• Hundreds of W>F neoepitopes were identified, primarily presented by HLA-A*24:02.
• A high-affinity TCR (TCR^TMBIM6W>F.1) was identified for the TMBIM6^W>F neoepitope, broadly expressed across cancer cell lines.
• TCR^TMBIM6W>F.1 T cells specifically activated by tryptophan-depleted cancer cells.
• In vivo studies demonstrated that TCR^MART1 T cells enhance cancer cell killing mediated by TCR^TMBIM6W>F.1 T cells via W>F neoepitope generation.

Conclusions:

• W>F neoepitopes represent shared, highly expressed, and immunogenic targets in cancer.
• These neoepitopes hold potential for advancing adoptive T cell therapy by overcoming current limitations.