HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy
Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against...
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2021-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/4/e002071.full |
| _version_ | 1818918537122545664 |
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| author | Jian Wang Michael Weller Roland Martin Holger Moch Julia Velz Luca Regli Hans-Georg Rammensee Linus Backert Oliver Kohlbacher Ana Marcu Leon Bichmann Leon Kuchenbecker Daniel Johannes Kowalewski Lena Katharina Freudenmann Lena Mühlenbruch András Szolek Maren Lübke Philipp Wagner Tobias Engler Sabine Matovina Mathias Hauri-Hohl Konstantina Kapolou Juliane Sarah Walz Manuela Silginer Markus W. Löffler Florian Erhard Andreas Schlosser Stefan Stevanović Marian Christoph Neidert |
| author_facet | Jian Wang Michael Weller Roland Martin Holger Moch Julia Velz Luca Regli Hans-Georg Rammensee Linus Backert Oliver Kohlbacher Ana Marcu Leon Bichmann Leon Kuchenbecker Daniel Johannes Kowalewski Lena Katharina Freudenmann Lena Mühlenbruch András Szolek Maren Lübke Philipp Wagner Tobias Engler Sabine Matovina Mathias Hauri-Hohl Konstantina Kapolou Juliane Sarah Walz Manuela Silginer Markus W. Löffler Florian Erhard Andreas Schlosser Stefan Stevanović Marian Christoph Neidert |
| author_sort | Jian Wang |
| collection | DOAJ |
| description | Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level.Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing.Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference.Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org. |
| first_indexed | 2024-12-20T00:51:32Z |
| format | Article |
| id | doaj.art-5f3fc47c106b4ae084c10a3498b6514a |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-20T00:51:32Z |
| publishDate | 2021-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-5f3fc47c106b4ae084c10a3498b6514a2022-12-21T19:59:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-04-019410.1136/jitc-2020-002071HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapyJian Wang0Michael Weller1Roland Martin2Holger Moch3Julia Velz4Luca Regli5Hans-Georg Rammensee6Linus Backert7Oliver Kohlbacher8Ana Marcu9Leon Bichmann10Leon Kuchenbecker11Daniel Johannes Kowalewski12Lena Katharina Freudenmann13Lena Mühlenbruch14András Szolek15Maren Lübke16Philipp Wagner17Tobias Engler18Sabine Matovina19Mathias Hauri-Hohl20Konstantina Kapolou21Juliane Sarah Walz22Manuela Silginer23Markus W. Löffler24Florian Erhard25Andreas Schlosser26Stefan Stevanović27Marian Christoph Neidert286 Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich, Switzerland12 Clinical Neuroscience Center and Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland13 Neuroimmunology and MS Research Section, Department of Neurology, University Hospital Zürich, Switzerland, Germany11 Department of Pathology, Institute for Surgical Pathology, University Hospital, Zurich, SwitzerlandDepartment of Neurosurgery, University Hospital Zurich, Clinical Neuroscience Center, University of Zurich, Zurich, SwitzerlandDepartment of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, Zurich, SwitzerlandAff4 grid.10392.390000000121901447Department of Immunology, Institute for Cell BiologyUniversity of Tübingen Tübingen GermanyAff281 grid.10392.390000000121901447Eberhard-Karls-Universität Tübingen, WSI/ZBIT, Applied Bioinformatics Group Tubingen Baden-Wurttemberg GermanyAff281 grid.10392.390000000121901447Eberhard-Karls-Universität Tübingen, WSI/ZBIT, Applied Bioinformatics Group Tubingen Baden-Wurttemberg Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany3 Applied Bioinformatics, Department of Computer Science, University of Tübingen, Tübingen, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany3 Applied Bioinformatics, Department of Computer Science, University of Tübingen, Tübingen, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany5 Department of Obstetrics and Gynecology, University Hospital of Tübingen, Tübingen, Germany5 Department of Obstetrics and Gynecology, University Hospital of Tübingen, Tübingen, Germany7 Pediatric Stem Cell Transplantation, University Children’s Hospital Zurich, Zurich, Switzerland8 Clinical Neuroscience Center and Department of Neurosurgery, University Hospital and University of Zurich, Zurich, Switzerland1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany12 Clinical Neuroscience Center and Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany15 Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Würzburg, Bayern, Germany16 Rudolf Virchow Center - Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Würzburg, Würzburg, Germany1 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany8 Clinical Neuroscience Center and Department of Neurosurgery, University Hospital and University of Zurich, Zurich, SwitzerlandBackground The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level.Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing.Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference.Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org.https://jitc.bmj.com/content/9/4/e002071.full |
| spellingShingle | Jian Wang Michael Weller Roland Martin Holger Moch Julia Velz Luca Regli Hans-Georg Rammensee Linus Backert Oliver Kohlbacher Ana Marcu Leon Bichmann Leon Kuchenbecker Daniel Johannes Kowalewski Lena Katharina Freudenmann Lena Mühlenbruch András Szolek Maren Lübke Philipp Wagner Tobias Engler Sabine Matovina Mathias Hauri-Hohl Konstantina Kapolou Juliane Sarah Walz Manuela Silginer Markus W. Löffler Florian Erhard Andreas Schlosser Stefan Stevanović Marian Christoph Neidert HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy Journal for ImmunoTherapy of Cancer |
| title | HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy |
| title_full | HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy |
| title_fullStr | HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy |
| title_full_unstemmed | HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy |
| title_short | HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy |
| title_sort | hla ligand atlas a benign reference of hla presented peptides to improve t cell based cancer immunotherapy |
| url | https://jitc.bmj.com/content/9/4/e002071.full |
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