PD-1 Blockade Reinvigorates Bone Marrow CD8 + T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors
Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma. Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examin...
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Veröffentlicht in: | Clinical cancer research 2020-04, Vol.26 (7), p.1644-1655 |
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Zusammenfassung: | Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.
Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8
T cells and their functional restoration by
treatment with anti-PD-1 and TGFβ inhibitors.
We confirmed the upregulation of PD-1 and PD-L1 expression in CD8
T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8
T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype. These results were also observed in BM CD8
T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8
T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8
T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8
T cells from multiple myeloma patients in the presence of inhibitors of TGFβ, which was overexpressed by myeloma cells.
Our findings indicate that combined blockade of PD-1 and TGFβ may be useful for the treatment of multiple myeloma. |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-19-0267 |