Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naive Multiple Myeloma

Welters, Carlotta; Cobo, Maria Fernanda Lammoglia; Stein, Christian Alexander; Hsu, Meng-Tung; Ben Hamza, Amin; Penter, Livius; Chen, Xiaojing; Buccitelli, Christopher; Popp, Oliver; Mertins, Philipp; Dietze, Kerstin; Bullinger, Lars; Moosmann, Andreas; Blanc, Eric; Beule, Dieter; Gerbitz, Armin; Strobel, Julian; Hackstein, Holger; Rahn, Hans-Peter; Dornmair, Klaus; Blankenstein, Thomas und Hansmann, Leo (2022): Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naive Multiple Myeloma. In: Cancer Immunology Research, Bd. 10, Nr. 11: S. 1407-1419

Abstract

Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiologic relevance, the roles of bone mar-row-infiltrating T cells in treatment-naive patients are incom-pletely understood. We investigated whether clonally expanded T cells (i) were detectable in multiple myeloma bone marrow, (ii) showed characteristic immune phenotypes, and (iii) whether dominant clones recognized antigens selectively presented on multiple myeloma cells. Single-cell index sorting and T-cell receptor (TCR) ali sequencing of bone marrow T cells from 13 treatment-naive patients showed dominant clonal expansion within CD8 thorn cytolytic effector compartments, and only a minor-ity of expanded T-cell clones expressed the classic immune-checkpoint molecules PD-1, CTLA-4, or TIM-3. To identify their molecular targets, TCRs of 68 dominant bone marrow clones from five selected patients were reexpressed and incubated with multiple myeloma and non-multiple myeloma cells from corresponding patients. Only 1 of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C- restricted, self-peptide-specific and could be activated by mul -ti ple myeloma cells of multiple patients. The remaining domi-nant T-cell clones did not recognize multiple myeloma cells and were, in part, specific for antigens associated with chronic viral infections. In conclusion, we showed that dominant bone mar-row T-cell clones in treatment-naive patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classic immune-checkpoint molecules. Our data provide experimental context for experiences from clinical immune-checkpoint inhibition trials and will inform future T cell-dependent therapeutic strategies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2326-6066
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198