Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom.
Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
Cancer Res. 2019 Apr 1;79(7):1480-1492. doi: 10.1158/0008-5472.CAN-18-2244. Epub 2019 Jan 23.
A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3 mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3 mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade. http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.
联合治疗方法需要改善肿瘤免疫浸润和患者对针对负调节受体的免疫检查点抑制剂的反应。半乳糖凝集素-3 是一种β-半乳糖苷结合凝集素，在侵袭性癌症的肿瘤微环境中高度表达，其表达与不良生存相关，尤其是在非小细胞肺癌（NSCLC）患者中。为了研究半乳糖凝集素-3 抑制在 NSCLC 中的作用，我们使用遗传和药理学方法测试了半乳糖凝集素-3 耗竭对同源小鼠肺腺癌和人肺腺癌异种移植物的影响。与同源 C57/Bl6 野生型小鼠相比，半乳糖凝集素-3 小鼠的肿瘤明显更小、更少且转移更少。巨噬细胞消融会减缓肿瘤生长，而用半乳糖凝集素-3 阳性骨髓重建则会恢复半乳糖凝集素-3 小鼠的肿瘤生长，表明巨噬细胞是抗肿瘤反应的主要驱动因素。新型小分子半乳糖凝集素-3 抑制剂 GB1107 的口服给药可减少人源和鼠源肺腺癌的生长并阻断同源模型中的转移。GB1107 治疗增加了肿瘤 M1 巨噬细胞极化和 CD8 T 细胞浸润。此外，GB1107 增强了 PD-L1 免疫检查点抑制剂的作用，增加了细胞毒性（IFNγ、颗粒酶 B、穿孔素-1、Fas 配体）和凋亡（cleaved caspase-3）效应分子的表达。总之，半乳糖凝集素-3 是肺腺癌进展的重要调节剂。所提出的新型半乳糖凝集素-3 抑制剂可提供有效、无毒的单药治疗，或与免疫检查点抑制剂联合使用，以增强肺腺癌和潜在其他侵袭性癌症的免疫浸润和反应。意义：一种新型、口服活性的半乳糖凝集素-3 拮抗剂可抑制肺腺癌的生长和转移，并增强对 PD-L1 阻断的反应。http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg。
