Champagne et al. demonstrated that prolonged IFNγ exposure and the resulting IDO1 induction create a tryptophan-depleted TME, driving the formation of tryptophan-to-phenylalanine (W>F) substitution neoepitopes. Immunopeptidomic analyses identified hundreds of these neoepitopes, with TMBIM6W>F emerging as a broadly expressed, HLA-A*24:02-restricted target. Engineered TCRTMBIM6W>F.1 T cells showed TMBIM6W>F specificity and robust cytotoxicity towards cancer cells pre-treated with IFNγ. In vivo, TCRMART1-driven preconditioning enhanced W>F neoepitope generation, amplifying TCRTMBIM6W>F.1-mediated tumor cell killing.
Contributed by Shishir Pant
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 (TCRTMBIM6W>F.1) possessing high affinity and specificity toward TMBIM6W>F/HLA-A∗24:02, the inducible W>F neoepitope with the broadest expression across cancer cell lines. TCRTMBIM6W>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 TCRMART1 T cells promote cancer cell killing by TCRTMBIM6W>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.
Author Info: (1) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Cancer Immunology, Institute for Cancer Research, Os
Author Info: (1) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (3) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (10) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (16) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (17) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (18) Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA), the Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA), the Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Division of Pharmacology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) NKI Proteomics facility, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. Electronic address: johanna.olweus@medisin.uio.no. (24) Division of Oncogenomics, Oncode institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Erasmus MC, Department of Genetics, Rotterdam University, Rotterdam, the Netherlands. Electronic address: r.agami@nki.nl.
