Cancer-specific T helper shared and neo-epitopes uncovered by expression of the MHC class II master regulator CIITA

Hos, B.J.; Tondini, E.; Camps, M.G.M.; Rademaker, W.; Bulk, J. van den; Ruano, D.; Janssen, G.M.C.; Ru, A.H. de; Elsen, P.J. van den; Miranda, N.F.C.C. de; Veelen, P.A. van; Ossendorp, F.

doi:doi:10.1016/j.celrep.2022.111485

We report an approach to identify tumor-specific CD4+ T cell neo-epitopes of both mouse and human cancer cells by analysis of major histocompatibility complex (MHC) class II-eluted natural peptides. MHC class II -presented peptide sequences are identified by introducing the MHC class II transactivator (CIITA) in tumor cells that were originally MHC class II negative. CIITA expression facilitates cell-surface expression of MHC class II molecules and the appropriate peptide-loading machinery. Peptide elution of purified MHC class II molecules and subsequent mass spectrometry reveals oncoviral-and neo-epitopes as well as shared epitopes. Immunological relevance of these epitopes is shown by natural presentation by dendritic cells and immunogenicity. Synthetic peptide vaccination induced functional CD4+ T cell responses, which helped tu-mor control in vivo. Thus, this CIITA transfection approach aids to identify relevant T helper epitopes pre-sented by any MHC class II allele that would...Show moreWe report an approach to identify tumor-specific CD4+ T cell neo-epitopes of both mouse and human cancer cells by analysis of major histocompatibility complex (MHC) class II-eluted natural peptides. MHC class II -presented peptide sequences are identified by introducing the MHC class II transactivator (CIITA) in tumor cells that were originally MHC class II negative. CIITA expression facilitates cell-surface expression of MHC class II molecules and the appropriate peptide-loading machinery. Peptide elution of purified MHC class II molecules and subsequent mass spectrometry reveals oncoviral-and neo-epitopes as well as shared epitopes. Immunological relevance of these epitopes is shown by natural presentation by dendritic cells and immunogenicity. Synthetic peptide vaccination induced functional CD4+ T cell responses, which helped tu-mor control in vivo. Thus, this CIITA transfection approach aids to identify relevant T helper epitopes pre-sented by any MHC class II allele that would be otherwise very difficult to predict and reveals important tar-gets for cancer immunotherapy.Show less

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Cancer-specific T helper shared and neo-epitopes uncovered by expression of the MHC class II master regulator CIITA