TY  - JOUR
A1  - Marcu, Ana
A1  - Bichmann, Leon
A1  - Kuchenbecker, Leon
A1  - Kowalewski, Daniel Johannes
A1  - Freudenmann, Lena Katharina
A1  - Backert, Linus
A1  - Mühlenbruch, Lena
A1  - Szolek, András
A1  - Lübke, Maren
A1  - Wagner, Philipp
A1  - Engler, Tobias
A1  - Matovina, Sabine
A1  - Wang, Jian
A1  - Hauri-Hohl, Mathias
A1  - Martin, Roland
A1  - Kapolou, Konstantina
A1  - Walz, Juliane Sarah
A1  - Velz, Julia
A1  - Moch, Holger
A1  - Regli, Luca
A1  - Silginer, Manuela
A1  - Weller, Michael
A1  - Löffler, Markus W.
A1  - Erhard, Florian
A1  - Schlosser, Andreas
A1  - Kohlbacher, Oliver
A1  - Stevanović, Stefan
A1  - Rammensee, Hans-Georg
A1  - Neidert, Marian Christoph
T1  - HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy
JF  - Journal for ImmunoTherapy of Cancer
N2  - 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 .
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370160
VL  - 9
ER  -