PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors
PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors
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DOI：
10.1158/1078-0432.ccr-19-0267
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发表时间：
2020-04-01
影响因子：
11.5
通讯作者：
Shin, Eui-Cheol
中科院分区：
文献类型：
--
作者：
Kwon, Minsuk;Kim, Chang Gon;Shin, Eui-Cheol
目的：免疫检查点抑制剂在多种恶性疾病中显示出治疗效果。然而，抗程序性死亡(PD)-1治疗在多发性骨髓瘤中尚未显示出临床疗效。实验设计：从77例新诊断的多发性骨髓瘤患者中获得骨髓（BM）单个核细胞。我们检测了免疫检查点受体在BM CD8(+) T细胞中的表达，并通过抗pd -1和TGF β抑制剂体外治疗检测了它们的功能恢复。结果：我们证实了多发性骨髓瘤患者骨髓中CD8(+) T细胞和骨髓瘤细胞中PD-1和PD-L1的表达上调。多发性骨髓瘤患者骨髓中表达pd -1的CD8(+) T细胞共表达其他检查点抑制受体，并表现出终末分化表型。在骨髓瘤抗原NY-ESO-1和HM1.24特异性的骨髓CD8(+) T细胞中也观察到这些结果。来自多发性骨髓瘤患者的BM CD8(+) T细胞在T细胞受体刺激下表现出增殖和细胞因子产生的减少。然而，抗PD-1并没有增加多发性骨髓瘤患者BM CD8(+) T细胞的增殖，这表明单独阻断PD-1很难逆转多发性骨髓瘤中的T细胞衰竭。有趣的是，在骨髓瘤细胞过度表达TGF β抑制剂存在的情况下，抗pd -1显著增加多发性骨髓瘤患者BM CD8(+) T细胞的增殖。结论：我们的研究结果表明，联合阻断PD-1和TGFb可能对多发性骨髓瘤的治疗有用。
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.