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.
Background: Signaling Lymphocyte Activation Marker Family member 7 (SLAMF7) is highly expressed on human plasma cells and malignant myeloma cells, which is a therapeutic target for the anti-SLAMF7 antibody elotuzumab. Lower expression of SLAMF7 is found in NK cells, NK-like T cells, CD8+ T cells, activated monocytes and dendritic cells. With the exception of plasmablastic lymphoma and multiple myeloma, SLAMF7 was never been reported to be expressed in other malignant hematological diseases. Aims: This prompted us to examine the expression of SLAMF7 also in T-cell lymphoma, NK/T-cell lymphoma, NK cell derived large granular lymphocyte (NK-LGL) and T-cell LGL. Methods We examined in biopsy tissue or blood samples of 11 patients with histologically proven NK/T-cell lymphomas, T-cell lymphoma, T-ALL, non-malignant Kikuchi necrotizing lymphadenitis, NK-LGL and T-LGL SLAMF7 expression by immunohistochemistry (IHC) or flow cytometry. We defined SLAMF7 as positive if we detected SLAMF7 expression in at least 20% of lymphoma cells by IHC or 10% by flow cytometer. As positive controls for SLAMF7 expression we used biopsy tissue from patients with multiple myeloma. Results: Here we found a strong expression of SLAMF7 by IHC in all 3 patients with NK/T-cell lymphoma, whereas no expression by IHC was found on T-cell lymphoma biopsy tissue of 3 patients with T-cell lymphoma and of 1 patient with T-ALL. Another patient who was suspected with T-cell lymphoma but later diagnosed as non-malignant Kikuchi necrotizing lymphadenitis, was tested weak positive for SLAMF7 expression by IHC as shown in table 1. Strong SLAMF7 expression was specific to lymphoma tissue in a patient with NK/T-cell lymphoma but not found in the surrounding healthy tissue of nasal epithelial cells as shown in figure 1, which identifies SLAMF7 as a suitable biomarker for NK/T-cell lymphoma. We detected SLAMF7 also in a patient with CD3-/CD56+/CD16+ NK-LGL cells and a further patient with CD3+/CD56+/CD8+ T-LGL by flow cytometer. Interestingly, 100% of NK-LGL cells (38,9% of all mononucleated cells in peripheral blood) and all T-LGL cells (17,2% of all mononucleated cells in peripheral blood) were SLAMF7 positive.Summary/Conclusion: Here we report for the first time expression of SLAMF7 in NK/T-cell lymphoma and NK-LGL and T-LGL, which has clinical relevance because it extends possible immunotherapy to SLAMF7 inhibitor elotuzumab. SLAMF7 might also be a suitable target for CAR-T cell therapies as already used successfully in multiple myeloma trials. Nevertheless, it might be useful as a biomarker for NK/T-cell lymphomas and LGL, too.
The impact of MYC locus aberrations on the outcome of multiple myeloma (MM) patients is still a matter of debate. The aim of this study was to further investigate their influence on the survival of MM patients treated with high-dose chemotherapy. Our data suggest that the favorable prognosis factor
The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma.
