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. 2020 Apr 1;26(7):1644-1655.
doi: 10.1158/1078-0432.CCR-19-0267. Epub 2020 Jan 15.

PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

Minsuk Kwon #  1 , Chang Gon Kim #  1 , Hoyoung Lee #  2 , Hyunsoo Cho  3 , Youngun Kim  1 , Eung Chang Lee  4 , Seong Jin Choi  1 , Junsik Park  1 , In-Ho Seo  1 , Bjarne Bogen  5 , Ik-Chan Song  6 , Deog-Yeon Jo  6 , Jin Seok Kim  3 , Su-Hyung Park  2 , Inhak Choi  7 , Yoon Seok Choi  8 , Eui-Cheol Shin  9
Affiliations

PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

Minsuk Kwon et al. Clin Cancer Res. .

Abstract

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 TGFβ 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 TGFβ, which was overexpressed by myeloma cells.

Conclusions: Our findings indicate that combined blockade of PD-1 and TGFβ may be useful for the treatment of multiple myeloma.

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