Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiological relevance, the roles of bone marrow infiltrating T cells in treatment-naïve patients are incompletely 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)αβ sequencing of bone marrow T cells from 13 treatment-naïve patients showed dominant clonal expansion within CD8+ cytolytic effector compartments, and only a minority of expanded T-cell clones expressed the classical 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 re-expressed and incubated with multiple myeloma and non multiple myeloma cells from corresponding patients. Only one out of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C-restricted, self-peptide-specific, and could be activated by multiple myeloma cells of multiple patients. The remaining dominant 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 marrow T-cell clones in treatment naïve patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classical 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.

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