Es triggering optimised T-cell responses toward immune-escaped tumoursAur ie Durgeau 1,two, Yasemin Virk1, Gwendoline Gros1, Elodie Voilin1, St hanie Corgnac 1, Fay l Djenidi1, J e Salmon3, Julien Adam4, Vincent de Montpr ille 1,5, Pierre Validire6, Soldano Ferrone7, Salem Chouaib1,15, Alexander Eggermont8, Jean-Charles Soria9, Fran is Lemonnier10, Eric Tartour 11, Nathalie Chaput12,13, Benjamin Besse14 Fathia Mami-Chouaib1234567890():,;Tumours frequently evade CD8 T-cell immunity by downregulating TAP. T-cell epitopes related with impaired peptide processing are immunogenic non-mutated neoneo-Inositol manufacturer antigens that emerge throughout tumour immune evasion. The preprocalcitonin (ppCT)16?5 neoepitope belongs to this category of antigens. Here we show that most human lung tumours display altered expression of TAP and frequently express ppCT self-antigen. We also show that ppCT involves HLA-A2-restricted epitopes that are processed by TAP-independent and -dependent pathways. Processing occurs in either the endoplasmic reticulum, by signal peptidase and signal peptide peptidase, or within the cytosol following release of a signal peptide precursor or retrotranslocation of a procalcitonin substrate by endoplasmic-reticulum-associated degradation. Remarkably, ppCT peptide-based immunotherapy induces efficient T-cell responses toward antigen processing and presenting machinery-impaired tumours transplanted into DL-��-Tocopherol Epigenetic Reader Domain HLA-A0201-transgenic mice and in NOD-scid-Il2rnull mice adoptively transferred with human PBMC. Thus, ppCT-specific T lymphocytes are promising effectors for therapy of tumours that have escaped immune recognition.UMR 1186, Integrative Tumour Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Fac. de M ecine, Univ. Paris-Sud, Universit?Paris-Saclay, 94805 Villejuif, France. two ElyssaMed, Paris Biotech Sant? 75014 Paris, France. three CNRS (Centre National de la Recherche Scientifique) UMR 8122, Gustave Roussy, Facult?de M ecine, Univ. Paris-Sud, Universit?Paris-Saclay, 94805 Villejuif, France. 4 INSERM U 981, Gustave Roussy, Facult?de M ecine, Univ. Paris-Sud, Universit?Paris-Saclay, 94805 Villejuif, France. 5 Service d’Anatomie Pathologique, Centre Chirurgical Marie-Lannelongue, 92350 Le-Plessis-Robinson, France. six Service d’Anatomie Pathologique, Institut Mutualiste Montsouris, 75014 Paris, France. 7 Department of Surgery, Massachusetts General Hospital, Harvard Healthcare College, Boston, MA 02114, USA. 8 Cancer Institute, Gustave Roussy Cancer Campus, Grand Paris, 94805 Villejuif, France. 9 Department of Drug Development (DITEP), Gustave Roussy, 94805 Villejuif, France. 10 D artement Endocrinologie, M abolisme et Diab e, Equipe Immunologie des Diab es, INSERM U1016, 75014 Paris, France. 11 INSERM U970, Paris Cardiovascular Analysis Centre, Universit?ParisDescartes, Sorbonne Paris Cit? Equipe Labellis Ligue Contre le Cancer, H ital Europ n Georges Pompidou, Service d’Immunologie Biologique, 75015 Paris, France. 12 Laboratory of Immunomonitoring in Oncology, and CNRS-UMS 3655 and INSERM-US23, Gustave Roussy Cancer Campus, Villejuif, France. 13 Facult?de Pharmacie, University Paris-Sud, F-92296 Chatenay-Malabry, France. 14 D artement de M ecine, Gustave Roussy, 94805 Villejuif, France. 15 Present address: Thumbay Institute for Precision Medicine, Gulf Health-related University, Ajman 4184, UAE. These authors contributed equally: Yasemin Virk, Gwendoline Gros. Correspondence and requests for components must be addressed to F.M.-C. (e mail: Fathia.Mami-Chouaib@gustaverou.
