Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Front Immunol. 2022 Aug 8;13:950134. doi: 10.3389/fimmu.2022.950134. eCollection 2022.
Hypomethylating agents (HMAs) are widely used in patients with higher-risk MDS not eligible for stem cell transplantation. However, the general response rate by HMAs is lesser than 50% in MDS patients, while the relapse rate is high. Emerging evidence indicates that demethylating effects committed by HMAs may facilitate the up-regulation of a range of immune checkpoints or cancer suppressor genes in patients with MDS, among which the programmed death protein 1 (PD-1) and its ligands are demonstrated to be prominent and may contribute to treatment failure and early relapse. Although results from preliminary studies with a limited number of enrolled patients indicate that combined administration of PD-1 inhibitor may yield extra therapeutic benefit in some MDS patients, identifications of this subgroup of patients and optimal timing for the anti-PD-1 intervention remain significant challenges. Dynamics of immune checkpoints and associated predictive values during HMA-treatment cycles remained poorly investigated. In this present study, expression levels of immune checkpoints PD-1 and its ligands PD-L1 and PD-L2 were retrospectively analyzed by quantitative PCR (Q-PCR) in a total of 135 myelodysplastic syndromes (MDS) cohort with higher-risk stratification. The prognostic value of dynamics of these immune checkpoints during HMA cycles was validated in two independent prospective cohorts in our center (NCT01599325 and NCT01751867). Our data revealed that PD-1 expression was significantly higher than that in younger MDS patients (age ≤ 60) and MDS with lower IPSS risk stratification (intermediate risk-1). A significantly up-regulated expression of PD-1 was seen during the first four HMA treatment cycles in MDS patients, while similar observation was not seen concerning the expression of PD-L1 or PD-L2. By utilizing binary logistic regression and receiver operating characteristic (ROC) models, we further identified that higher or equal to 75.9 PD-1 expressions after 2 cycles of HMA treatment is an independent negative prognostic factor in predicting acute myeloid leukemia (AML) transformation and survival. Collectively, our data provide rationales for monitoring the expression of PD-1 during HMA treatment cycles, a higher than 75.9 PD-1 expression may identify patients who will potentially benefit from the combined therapy of HMA and PD-1 inhibitors.
低甲基化药物（HMAs）广泛用于不适合干细胞移植的高危 MDS 患者。然而，MDS 患者对 HMAs 的总体反应率低于 50%，而复发率较高。新出现的证据表明，HMAs 所产生的去甲基化作用可能促进 MDS 患者一系列免疫检查点或抑癌基因的上调，其中程序性死亡蛋白 1（PD-1）及其配体被证明是突出的，可能导致治疗失败和早期复发。尽管初步研究的结果显示，在一些 MDS 患者中联合使用 PD-1 抑制剂可能会产生额外的治疗益处，但确定这类患者亚群和进行抗 PD-1 干预的最佳时机仍然是一个重大挑战。在 HMA 治疗周期中，免疫检查点的动态及其相关预测值仍未得到充分研究。在这项研究中，通过定量 PCR（Q-PCR）对 135 例高危分层的骨髓增生异常综合征（MDS）队列的免疫检查点 PD-1 及其配体 PD-L1 和 PD-L2 的表达水平进行了回顾性分析。在我们中心的两个独立前瞻性队列（NCT01599325 和 NCT01751867）中，验证了这些免疫检查点在 HMA 周期中的动态的预后价值。我们的数据显示，PD-1 的表达在年龄≤60 岁的年轻 MDS 患者和低 IPSS 风险分层（中危-1）的 MDS 患者中明显高于 MDS 患者。在 MDS 患者的前四个 HMA 治疗周期中，PD-1 的表达显著上调，而 PD-L1 或 PD-L2 的表达则没有观察到类似的变化。通过利用二项逻辑回归和受试者工作特征（ROC）模型，我们进一步发现，在 HMA 治疗 2 个周期后，PD-1 表达等于或高于 75.9%是预测急性髓系白血病（AML）转化和生存的独立不良预后因素。总之，我们的数据为监测 HMA 治疗周期中 PD-1 的表达提供了依据，PD-1 表达高于 75.9%可能可以识别出可能从 HMA 和 PD-1 抑制剂联合治疗中获益的患者。
