Department of Oncology/Hematology/Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Leukemia. 2014 May;28(5):993-1000. doi: 10.1038/leu.2013.310. Epub 2013 Oct 23.
The adaptive immune system is clearly capable of recognizing and attacking malignant plasma cells in patients with multiple myeloma (MM). However, MM patients evidence severe defects of humoral and cellular immunity, and it is likely that the profound immune dysregulation typical for this malignancy contributes to its eventual escape from natural immune control. One of the factors responsible for the immune dysfunction in MM might be the programmed death 1 (PD-1) protein. The physiological role of PD-1 is to guarantee T-cell homeostasis by limiting T-cell activation and proliferation. Accordingly, binding of the ligand PD-L1 to PD-1 expressed on the surface of activated T cells delivers an inhibitory signal, reducing cytokine production and proliferation. Using the same mechanism, PD-L1/PD-1 interactions have been shown in a number of animal models to confer tumor escape from immune control. Recently, clinical trials have suggested a significant therapeutic impact of PD-1/PD-L inhibition on a variety of solid tumors-for example, by the application of monoclonal antibodies. We show here that based on (1) the broad expression of PD-1 and its ligands in the microenvironment of myeloma, (2) data indicating an important role of the PD-1 pathway in the immune evasion by MM cells and (3) preclinical results providing a strong rationale for therapeutic PD-1/PD-L inhibition in this malignancy, MM may be very well suited for immunotherapy, for example, a monoclonal antibody, targeting PD-1 and/or its ligands.
适应性免疫系统显然能够识别和攻击多发性骨髓瘤（MM）患者中的恶性浆细胞。然而，MM 患者存在体液和细胞免疫的严重缺陷，很可能是这种恶性肿瘤特有的严重免疫失调导致其最终逃脱自然免疫控制。导致 MM 免疫功能障碍的因素之一可能是程序性死亡 1（PD-1）蛋白。PD-1 的生理作用是通过限制 T 细胞激活和增殖来保证 T 细胞的稳态。因此，配体 PD-L1 与表面表达的激活 T 细胞上的 PD-1 结合会传递抑制信号，减少细胞因子产生和增殖。同样的机制表明，PD-L1/PD-1 相互作用在许多动物模型中赋予了肿瘤逃避免疫控制的能力。最近的临床试验表明，PD-1/PD-L 抑制对多种实体瘤具有显著的治疗作用，例如通过应用单克隆抗体。我们在这里表明，基于（1）PD-1 及其配体在骨髓瘤微环境中的广泛表达，（2）表明 PD-1 途径在 MM 细胞免疫逃逸中具有重要作用的数据，以及（3）提供了在这种恶性肿瘤中进行治疗性 PD-1/PD-L 抑制的强有力理由的临床前结果，MM 可能非常适合免疫治疗，例如，针对 PD-1 和/或其配体的单克隆抗体。
