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T cell reactivity of MHC epitopes

ABSTRACT: By using >36,000 immunogenicity assay results, we developed a method to identify peptide-MHC complexes whose structural alignment facilitates T cell reaction. Our method accurately predicted neoepitopes for MHC II as well as MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types and on-therapy melanoma samples. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naÃƒÂ¯ve tumors in association with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure particularly with high TCR clonality and MHC II expression.

PROVIDER: EGAS00001006445 | EGA |

REPOSITORIES: EGA

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Project description:The appended raw files, csv files and other documents were deposited in the public domain in support for the publication "Expanding the MAPPs assay to accommodate MHC-II pan re-ceptors for improved predictability of potential T cell epitopes" by Katharina Hartman, Guido Steiner, Michel Siegel, Cary M. Looney, Timothy P. Hickling, Katharine Bray-French, Sebastian Springer, Celine Marban-Doran and Axel Ducret. The abstract is as follows: A critical step in the immunogenicity cascade is attributed to human leukocyte antigen (HLA) II presentation triggering T cell immune responses. The liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based major histocompatibility complex (MHC) II-associated peptide proteomics (MAPPs) assay is implemented during preclinical risk assessments to identify bio-therapeutic-derived T cell epitopes. Although studies indicate HLA-DP and HLA-DQ alleles are linked to immunogenicity, most MAPPs studies are restricted to HLA-DR as the dominant HLA II genotype due to lack of well-characterized immunoprecipitating antibodies. Herein we ad-dress this issue by testing various commercially-available clones of MHC-II pan (CR3/43, WR18, and Tu39), HLA-DP (B7/21), and HLA-DQ (SPV-L3 and 1a3) antibodies in the MAPPs assay, and characterizing identified peptides according to binding specificity. Our results reveal that HLA II receptor-precipitating reagents with similar reported specificities differ based on clonality and that MHC-II pan antibodies do not entirely exhibit pan-specific tendencies. Since no individual antibody clone is able to recover the complete HLA II peptide repertoire, we recommend a mixed strategy of clones L243, WR18, and SPV-L3 in a single immunoprecipitation step for more robust compound-specific peptide detection. Ultimately, our optimized MAPPs strategy im-proves the predictability and additional identification of T cell epitopes in immunogenicity risk assessments. The dataset is divided in two sections, one supporting the figures 1-4, the other one supporting the figure 5-6. The collective data has aslo be used to generate the supplementary tables S1-S9.

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T cell reactivity of MHC epitopes

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