Selective elimination of immunosuppressive T cells in patients with multiple myeloma

Mohamed H S Awwad; Abdelrahman Mahmoud; Heiko Bruns; Hakim Echchannaoui; Katharina Kriegsmann; Raphael Lutz; Marc S Raab; Uta Bertsch; Markus Munder; Anna Jauch; Katja Weisel; Bettina Maier; Niels Weinhold; Hans Jürgen Salwender; Volker Eckstein; Mathias Hänel; Roland Fenk; Jan Dürig; Benedikt Brors; Axel Benner; Carsten Müller-Tidow; Hartmut Goldschmidt; Michael Hundemer

doi:10.1038/s41375-021-01172-x

Selective elimination of immunosuppressive T cells in patients with multiple myeloma

Leukemia. 2021 Sep;35(9):2602-2615. doi: 10.1038/s41375-021-01172-x. Epub 2021 Feb 17.

Authors

Mohamed H S Awwad¹, Abdelrahman Mahmoud^{2

3}, Heiko Bruns⁴, Hakim Echchannaoui^{5

6}, Katharina Kriegsmann¹, Raphael Lutz¹, Marc S Raab^{1

7}, Uta Bertsch^{1

8}, Markus Munder⁵, Anna Jauch⁹, Katja Weisel¹⁰, Bettina Maier¹, Niels Weinhold¹, Hans Jürgen Salwender¹¹, Volker Eckstein¹, Mathias Hänel¹², Roland Fenk¹³, Jan Dürig¹⁴, Benedikt Brors^{2

8}, Axel Benner¹⁵, Carsten Müller-Tidow^{1

8

16}, Hartmut Goldschmidt^{1

8}, Michael Hundemer¹⁷

Affiliations

¹ Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
² Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
³ Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
⁴ Department of Hematology and Oncology, Erlangen University Hospital, Erlangen, Germany.
⁵ Third Department of Medicine, University Cancer Center (UCT), University Medical Center (UMC) of the Johannes Gutenberg University, Erlangen, Germany.
⁶ German Cancer Consortium (Dktk), Partner Site Frankfurt/Mainz, Mainz, Germany.
⁷ Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, 69120, Heidelberg, Germany.
⁸ National Center for Tumor Diseases, Heidelberg University, Heidelberg, Germany.
⁹ Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Department of Oncology, Hematology and BMT, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany.
¹² Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.
¹³ Department of Hematology, Oncology and Clinical Immunology, Düsseldorf University, Hamburg, Germany.
¹⁴ Department of Hematology, Essen University, Hamburg, Germany.
¹⁵ Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Molecular Medicine Partnership Unit, Heidelberg University Hospital, EMBL, Heidelberg, Germany.
¹⁷ Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany. michael.hundemer@med.uni-heidelberg.de.

Abstract

Elimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8⁺CD28^-CD57⁺ Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7⁺CD8⁺ T cells exhibited decreased immunoreactivity towards the MART-1_aa26-35*A27L antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7⁺CD8⁺ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8⁺ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.

Publication types

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

MeSH terms

Adult
Aged
Animals
Antibodies, Monoclonal, Humanized / therapeutic use*
Antineoplastic Agents / therapeutic use
Apoptosis
Cell Proliferation
Female
Humans
Lymphocyte Depletion / methods*
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Multiple Myeloma / immunology*
Multiple Myeloma / pathology
Multiple Myeloma / therapy
Prognosis
Signaling Lymphocytic Activation Molecule Family / genetics
Signaling Lymphocytic Activation Molecule Family / metabolism*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal, Humanized
Antineoplastic Agents
SLAMF7 protein, human
Signaling Lymphocytic Activation Molecule Family
elotuzumab