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

Welters C, Lammoglia Cobo MF, Stein CA, Hsu MT, Ben Hamza A, Penter L, Chen X, Buccitelli C, Popp O, Mertins P, Dietze K, Bullinger L, Moosmann A, Blanc E, Beule D, Gerbitz A, Strobel J, Hackstein H, Rahn HP, Dornmair K, Blankenstein T, Hansmann L (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cancer Immunology Research Cancer Immunology Research

Book Volume: 10

Pages Range: 1407-1419

Journal Issue: 11

DOI: 10.1158/2326-6066.CIR-22-0434

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 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 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 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 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.

Authors with CRIS profile

Julian Strobel Department of Transfusion Medicine and Haemostaseology Holger Hackstein Professur für Transfusionsmedizin und Cell-Engineering

Involved external institutions

Freie Universität Berlin DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Klinikum der Universität München DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Berliner Institut für Gesundheitsforschung (BIH) DE Germany (DE) University of Toronto CA Canada (CA)

How to cite

APA:

Welters, C., Lammoglia Cobo, M.F., Stein, C.A., Hsu, M.T., Ben Hamza, A., Penter, L.,... Hansmann, L. (2022). Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naïve Multiple Myeloma. Cancer Immunology Research, 10(11), 1407-1419. https://doi.org/10.1158/2326-6066.CIR-22-0434

MLA:

Welters, Carlotta, et al. "Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naïve Multiple Myeloma." Cancer Immunology Research 10.11 (2022): 1407-1419.

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