Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215007, China.
Central Laboratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
Clin Transl Oncol. 2023 Nov;25(11):3188-3202. doi: 10.1007/s12094-023-03187-5. Epub 2023 Apr 28.
The efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model.
The effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage.
Anagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2.
Anagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC.
程序性细胞死亡配体 1（PD-L1）抗体等免疫检查点抑制剂在非小细胞肺癌（NSCLC）中的疗效有限，推荐与其他疗法联合使用。二肽基肽酶 4（DPP4）抑制剂是一类小分子抑制剂，对治疗 2 型糖尿病非常有效。新出现的证据表明 DPP4 抑制剂是一种免疫调节剂，可调节固有和适应性免疫的各个方面。我们评估了 DPP4 抑制剂（阿那格列汀）与 PD-L1 阻断剂在 NSCLC 小鼠模型中的联合应用。
评估了抗 PD-L1 与阿那格列汀联合应用对 NSCLC 皮下小鼠模型的疗效。通过流式细胞术分析肿瘤浸润免疫细胞。从 C57BL/6 小鼠的骨髓中分离出骨髓源性单核细胞，在体外研究阿那格列汀对巨噬细胞分化和极化的潜在作用机制。
阿那格列汀通过抑制肿瘤微环境中的巨噬细胞形成和 M2 极化，显著提高了 PD-L1 抗体单药治疗的疗效。在机制上，阿那格列汀通过抑制巨噬细胞集落刺激因子诱导的 NOX1 和 NOX2 表达来抑制骨髓单核细胞中活性氧的产生，减少晚期 ERK 信号通路的激活，并抑制单核细胞-巨噬细胞分化。然而，在 M1 巨噬细胞极化过程中，脂多糖和干扰素-γ与相应受体相互作用会重新激活这种抑制作用，但在 M2 中不会。
阿那格列汀通过抑制巨噬细胞分化和 M2 巨噬细胞极化，可增强 NSCLC 中 PD-L1 阻断的疗效，联合治疗可能是治疗 PD-L1 阻断治疗耐药的 NSCLC 患者的一种有前途的策略。
