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

 Minsuk Kwon  ;  Chang Gon Kim  ;  Hoyoung Lee  ;  Hyunsoo Cho  ;  Youngun Kim  ;  Eung Chang Lee  ;  Seong Jin Choi  ;  Junsik Park  ;  In-Ho Seo  ;  Bjarne Bogen  ;  Ik-Chan Song  ;  Deog-Yeon Jo  ;  Jin Seok Kim  ;  Su-Hyung Park  ;  Inhak Choi  ;  Yoon Seok Choi  ;  Eui-Cheol Shin 
 CLINICAL CANCER RESEARCH, Vol.26(7) : 1644-1655, 2020-04 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal / pharmacology* ; Bone Marrow / drug effects ; Bone Marrow / immunology* ; Bone Marrow / pathology ; CD8-Positive T-Lymphocytes / immunology* ; Cells, Cultured ; Female ; Humans ; Male ; Middle Aged ; Multiple Myeloma / drug therapy* ; Multiple Myeloma / immunology ; Multiple Myeloma / pathology ; Programmed Cell Death 1 Receptor / antagonists & inhibitors* ; Programmed Cell Death 1 Receptor / immunology ; Receptors, Antigen, T-Cell / immunology* ; Transforming Growth Factor beta / antagonists & inhibitors* ; Transforming Growth Factor beta / metabolism
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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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cho, Hyunsoo(조현수) ORCID logo https://orcid.org/0000-0003-2651-6403
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