The Human Immunopeptidome Project: A Roadmap to Predict and Treat Immune Diseases

Kuchenbecker

et al. 2019

Preprint

ABSTRACTThe human leukocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Here, we describe the HLA Ligand Atlas, an extensive collection of mostly matched HLA-I and -II ligandomes from 225 benign samples (29 tissues, 21 subjects). The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 89,853 HLA-I- and 140,861 HLA-II ligands. We observe that the immunopeptidomes differ considerably between tissues and individuals on both source protein and HLA-ligand level. 1,407 HLA-I ligands stem from non-canonical genomic regions. We highlight the importance of comparatively analyzing both benign and malignant tissues to inform tumor association, based on a case study in three glioblastoma patients. The resource provides insights into applied and basic immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy, and autoimmunity. It is publicly available at www.hla-ligand-atlas.org.

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The HLA Ligand Atlas - A resource of natural HLA ligands presented on benign tissues

Marcu¹,

Kuchenbecker

et al. 2019

Preprint

“…However, the allotypic peptides might be a better reference as demonstrated in this study. The search for a reliable internal standard is an important prerequisite to ensure the comparability and robustness of immunopeptidomic analysis and is especially relevant for promising applications such as quantitative immunopeptidomics 47,48 . So far, protocols exist for the validation of LC-MS/MS based immunopeptidomics pipelines according to pharmaceutical good manufacturing practices (GMP) for peptide identification 31 .…”

Section: Discussionmentioning

confidence: 99%

An innovative approach for HLA typing, molecular tumor testing and the validation of tumor exclusive antigens

Ghosh

Scheid

et al. 2020

Preprint

The immunopeptidome, representing the point of contact between somatic and T cells, is key for adaptive immunity. Each presented peptide holds an abundance of information not yet well understood. Up to now, the scientific focus has been the definition of pathogenic or tumor derived epitopes and the deconvolution of HLA peptide motifs of the entire immunopeptidome. Here we go one step further and assess the properties of individual peptides to identify defined HLA allotype-specific and frequently presented peptides. Such allotypic peptides represent a versatile tool to determine HLA allotypes or serve as internal standard for characterization of cancer antigens and differentially processed antigens. Finally, individual tissue-and dignity-specific antigens were defined, and the latter were successfully implemented for molecular tumor testing.Using mass spectrometry based immunopeptidomics a database was generated consisting of ~900 HLA-typed samples. The identified allotypic peptides enabled a HLA class I allotype determination, which was 95% correct in our in-house dataset and 98% in an external dataset.These abundant peptides were implemented as internal standard for a semi-quantitative investigation of established tumor antigens and antigens processed differentially in malignant and benign tissue. Defined dignity-specific antigens allowed a 87% correct tumor detection across numerous tumor types.In summary, we describe a machine learning approach for mining immunopeptidomic data in order to develop a classification method, allowing to differentiate HLA class I-allotypes of a sample or distinguish between healthy and malignant state of tissues. Furthermore, based on this method, we developed a procedure for the validation of tumor exclusive antigens. Our results support classification of immunopeptidomic data sets using machine learning and highlight their potential utility for biomarker development.

“…In this context, jawed vertebrates evolved an important antigen processing and presentation system capable of presenting thousands of different MHC class I peptides on the surface of virtually any nucleated cells (Neefjes et al, 2011). In mammals, around 200 different cell types are decorated by large repertoires of self-MHC-I-associated peptides, collectively referred to as the mammalian MHC-I immunopeptidome (MHC-Ii) (Caron et al, 2017;Vizcaíno et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Global Analysis of the Mammalian MHC class I Immunopeptidome at the Organism-Wide Scale

Kubiniok

Marcu

et al. 2020

Preprint

Self Cite

Understanding the molecular principles that govern the composition of the mammalian MHC-I immunopeptidome (MHC-Ii) across different primary tissues is fundamentally important to predict how T cell respond in different contexts in vivo. Here, we performed a global analysis of the mammalian MHC-Ii from 29 and 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, -B and -C allotypes do not contribute evenly to the global composition of the MHC-Ii across multiple human tissues. Second, we found that peptides that are presented in a tissue-dependent and -independent manner share very distinct properties. Third, we discovered that proteins that were evolutionarily hyperconserved represent the primary source of the MHC-Ii at the organism-wide scale. Finally, we uncovered a remarkable antigen processing and presentation network that may drive the high level of heterogeneity of the MHC-Ii across different tissues in mammals. This study opens up new avenues toward a system-wide understanding of antigen presentation in vivo and may serve as ground work to understand tissue-dependent T cell responses in autoimmunity, infectious diseases and cancer.