Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation
Julien Champagne, Morten M. Nielsen, Xiaodong Feng, Jasmine Montenegro Navarro, Abhijeet Pataskar, Rhianne Voogd, Lisanne Giebel, Remco Nagel, Nadine Berenst, Amos Fumagalli, Adva Kochavi, Domenica Lovecchio, Lorenzo Valcanover, Yuval Malka, Weiwen Yang, Maarja Laos, Yingqian Li, Natalie Proost, Marieke van de Ven, Olaf van Tellingen, Onno B. Bleijerveld, John B.A.G. Haanen, Johanna Olweus, Reuven Agami
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.