PD-1 blockade reinvigorates bone marrow CD8+ T cells from patients with multiple myeloma in the presence of TGF-b inhibitors.

Purpose: 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. Experimental Design: 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 ex vivo treatment with anti-PD-1 and TGF beta inhibitors. Results: 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 TGF beta, which was overexpressed by myeloma cells. Conclusions: Our findings indicate that combined blockade of PD-1 and TGFb may be useful for the treatment of multiple myeloma.