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

Abstract

Prolonged exposure to interferon-gamma (IFNγ) and the associated increased expression of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage of tryptophan in the cancer cells, which stimulates ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis. Here, we investigated whether such neoepitopes can be useful targets of adoptive T cell therapy. Immunopeptidomic analyses uncovered hundreds of W>F neoepitopes mainly presented by the HLA-A^∗24:02 allele. We identified a T cell receptor (TCR^TMBIM6W>F.1) possessing high affinity and specificity toward TMBIM6^W>F/HLA-A^∗24:02, the inducible W>F neoepitope with the broadest expression across cancer cell lines. TCR^TMBIM6W>F.1 T cells are activated by tryptophan-depleted cancer cells but not by non-cancer cells. Finally, we provide in vivo proof of concept for clinical application, whereby TCR^MART1 T cells promote cancer cell killing by TCR^TMBIM6W>F.1 T cells through the generation of W>F neoepitopes. Thus, neoepitopes arising from W>F substitution present shared and highly expressed immunogenic targets with the potential to overcome current limitations in adoptive T cell therapy.