Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini

TY - JOUR

T1 - Carfilzomib alters the HLA-presented peptidome of myeloma cells and impairs presentation of peptides with aromatic C-termini

AU - Kowalewski, D J

AU - Walz, S

AU - Backert, L

AU - Schuster, H

AU - Kohlbacher, O

AU - Weisel, K

AU - Rittig, S M

AU - Kanz, L

AU - Salih, H R

AU - Rammensee, H-G

AU - Stevanović, S

AU - Stickel, J S

PY - 2016/4/8

Y1 - 2016/4/8

N2 - Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.

AB - Recent studies suggest that multiple myeloma is an immunogenic disease, which might be effectively targeted by antigen-specific T-cell immunotherapy. As standard of care in myeloma includes proteasome inhibitor therapy, it is of great importance to characterize the effects of this treatment on HLA-restricted antigen presentation and implement only robustly presented targets for immunotherapeutic intervention. Here, we present a study that longitudinally and semi-quantitatively maps the effects of the proteasome inhibitor carfilzomib on HLA-restricted antigen presentation. The relative presentation levels of 4780 different HLA ligands were quantified in an in vitro model employing carfilzomib treatment of MM.1S and U266 myeloma cells, which revealed significant modulation of a substantial fraction of the HLA-presented peptidome. Strikingly, we detected selective down-modulation of HLA ligands with aromatic C-terminal anchor amino acids. This particularly manifested as a marked reduction in the presentation of HLA ligands through the HLA allotypes A*23:01 and A*24:02 on MM.1S cells. These findings implicate that carfilzomib mediates a direct, peptide motif-specific inhibitory effect on HLA ligand processing and presentation. As a substantial proportion of HLA allotypes present peptides with aromatic C-termini, our results may have broad implications for the implementation of antigen-specific treatment approaches in patients undergoing carfilzomib treatment.

KW - Antigen Presentation

KW - Biomarkers

KW - Cell Line, Tumor

KW - Cell Membrane

KW - Epitopes

KW - Epitopes, T-Lymphocyte

KW - HLA Antigens

KW - Histocompatibility Antigens Class I

KW - Humans

KW - Immunophenotyping

KW - Ligands

KW - Mass Spectrometry

KW - Multiple Myeloma

KW - Oligopeptides

KW - Peptides

KW - Proteasome Inhibitors

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/bcj.2016.14

DO - 10.1038/bcj.2016.14

M3 - SCORING: Journal article

C2 - 27058226

VL - 6

SP - e411

JO - BLOOD CANCER J

JF - BLOOD CANCER J

SN - 2044-5385

ER -