Laboratory Hematology/Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, Canada.
Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Canada.
J Hematol Oncol. 2018 Mar 27;11(1):46. doi: 10.1186/s13045-018-0589-1.
Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.
即使在最近的治疗方案进展之后，多发性骨髓瘤患者通常仍会产生耐药性和复发。在临床前模型中已经证明了靶向 PD-1/PD-L1 轴的相关性。PD-1 抑制剂的单药治疗效果令人失望，但与用于多发性骨髓瘤治疗的其他药物联合使用似乎有希望，并且正在进行临床试验。然而，最近人们对 PD-1 和 PD-L1 抑制剂与免疫调节剂联合治疗多发性骨髓瘤的安全性表示担忧，并且已经暂停了几项试验。因此，需要寻找其他药物组合或针对该途径的不同方法。包括多发性骨髓瘤在内的癌细胞上 PD-L1 的蛋白表达与内在侵袭性特征有关，而与免疫逃逸机制无关，从而为采用直接针对 PD-L1 蛋白表达的新策略提供了依据。调节 PD-L1 的转录和转录后调控的药物可能成为治疗多发性骨髓瘤的新的治疗策略，有助于增强其他药物的作用，或者与 PD-1/PD-L1 抑制剂联合使用，以避免与免疫调节剂的潜在问题组合。本综述将重点介绍多发性骨髓瘤中 PD-L1 表达的病理生理学，以及已显示可调节这种表达的药物。
