Hematology and Hematological Oncology Department, Provincial Hospital, 45-061 Opole, Poland.
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland.
Int J Mol Sci. 2023 Mar 17;24(6):5730. doi: 10.3390/ijms24065730.
Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4CD28 T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, our study clearly showed that the checkpoint level in CD4 T cells may significantly affect the time to MM progression concerning the treatment status. Therefore, when considering novel therapies and potent combinations, it should be taken into account that blocking PD-1 rather than CTLA-4 might be a beneficial form of immunotherapy for only a proportion of RRMM patients.
多发性骨髓瘤（MM）是一种以严重深度免疫功能障碍为特征的血液恶性肿瘤。因此，靶向免疫环境的药物（如免疫检查点抑制剂（ICIs））的疗效具有重要的临床意义。然而，几项在不同治疗组合中评估 MM 中 ICIs 的临床试验结果令人失望，显示出缺乏临床疗效和过多的副作用。在大多数 MM 患者中观察到的对 ICI 耐药的潜在机制仍在研究中。最近，我们证明了在活动性 MM 中 CD4 T 细胞上 PD-1 和 CTLA-4 的表达不当与不良的临床结局和治疗状态有关。本研究的目的是确定免疫检查点表达评估作为治疗抑制剂反应的预测生物标志物的有用性。为此，除了流式细胞术估计的检查点表达外，我们还根据检查点表达水平评估了不同临床阶段（疾病诊断和复发）的 MM 患者的无进展时间（TTP）；根据中位值选择了截止点（将患者分为低表达者和高表达者）。在此，我们证实了新诊断（ND）患者中调节性 PD-1、CTLA-4 受体和 CD69 标记物激活的缺陷水平，而复发/难治性患者（RR）则表现出其恢复的水平和反应性。此外，在 MM 中发现了大量衰老的 CD4CD28 T 细胞，主要在 NDMM 患者中。这些观察结果表明，MM CD4 T 细胞中存在两种功能障碍状态，在疾病诊断时以免疫衰老为主，在复发时以衰竭为主，因此意味着根据疾病阶段对外部受体阻断的反应不同。此外，我们发现 NDMM 患者中 CTLA-4 水平较低或 RRMM 患者中 PD-1 表达较高可能预示着早期复发。总之，我们的研究清楚地表明，CD4 T 细胞中的检查点水平可能会显著影响 MM 进展的时间，这与治疗状态有关。因此，在考虑新的治疗方法和有效的联合治疗时，应该考虑到阻断 PD-1 而不是 CTLA-4 可能是 RRMM 患者的一种有益的免疫治疗形式。
