Shen Shih-Chun, Dey Souvik, DuHadaway James B, Sutanto-Ward Erika, Hampton Maurice T, Kozlov Serguei V, Prendergast George C, Muller Alexander J
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
J Immunother Cancer. 2025 May 30;13(5):e011398. doi: 10.1136/jitc-2024-011398.
Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.
Pulmonary metastases seeded by orthotopically implanted 4T1 breast carcinoma cells were evaluated by confocal microscopy for the impact of both genetic and pharmacological IDO1 inhibition, alone or in combination with ischemia-directed cytotoxic agents, on markers of blood vessel density, hypoxia and cell death. Tumor immunogenicity and programmed death-ligand 1 (PD-L1) elevation were also evaluated. Quantitative analysis of these results was used to guide combinatorial treatment regimen development.
Inhibiting IDO1 activity resulted in reduced neovascular density and elevated hypoxia in pulmonary metastases for which host IFN-γ was essential while adaptive immunity was dispensable. The tumors were consequently sensitized to the cytotoxic activity of ischemia-targeted agents including the protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157, the dithiol oxidative antimetabolite TTL-315, and the hypoxia-activated prodrug evofosfamide. Evofosfamide provoked the greatest degree of immunogenic cell death, while hypoxia, among other stressors, induced PD-L1. Based on this information, synergistic improvement in median survival was demonstrated in mice with established lung metastases through combined administration of anti-programmed cell death protein-1 (PD-1) antibody with evofosfamide and the IDO1 inhibitor epacadostat.
Improving therapeutic outcomes for patients with lung tumors, arising either as primary lesions or metastatic colonies, is of vital clinical importance. Building on preclinical evidence for IDO1's role in promoting inflammatory neovascularization of lung tumors, this study demonstrates how the intratumoral ischemic stress elicited by IDO1 inhibition can potentiate the immunogenic cytotoxicity of ischemia-targeted agents to effectively leverage immune checkpoint blockade responsiveness to confer a synergistic survival benefit. These findings provide a novel perspective on how IDO1 inhibitors can impact tumor biology and open up new possibilities for therapeutic applications.
将吲哚胺2,3-双加氧酶1（IDO1）靶向疗法用于抗癌的策略，主要聚焦于IDO1在促进外周免疫耐受从而使肿瘤免受效应T细胞攻击方面的作用。然而，针对肺部原发性和转移性肿瘤发展的临床前研究发现，IDO1在引导对干扰素（IFN）-γ的负调节反应中发挥了此前未被重视的作用，这种反应会重新调整局部炎症环境以促进肿瘤新血管生成。了解如何通过治疗手段利用IDO1抑制剂破坏肿瘤微环境中炎症性新血管生成的能力，对于这些化合物未来的临床开发具有潜在影响。
通过共聚焦显微镜评估原位植入的4T1乳腺癌细胞所形成的肺转移灶，观察基因和药物抑制IDO1单独或与缺血导向的细胞毒性药物联合使用，对血管密度、缺氧和细胞死亡标志物的影响。还评估了肿瘤免疫原性和程序性死亡配体1（PD-L1）的升高情况。对这些结果进行定量分析，以指导联合治疗方案的制定。
抑制IDO1活性导致肺转移灶中的新血管密度降低和缺氧加剧，其中宿主IFN-γ至关重要，而适应性免疫则无关紧要。因此，肿瘤对缺血靶向药物的细胞毒性变得敏感，这些药物包括蛋白激酶R样内质网激酶（PERK）抑制剂GSK2656157、二硫醇氧化抗代谢物TTL-315以及缺氧激活前药依沃福酰胺。依沃福酰胺引发的免疫原性细胞死亡程度最高，而缺氧等应激源会诱导PD-L1。基于这些信息，通过联合给予抗程序性细胞死亡蛋白1（PD-1）抗体、依沃福酰胺和IDO1抑制剂伊帕司他，在已建立肺转移的小鼠中证明了中位生存期有协同改善。
改善原发性或转移性肺肿瘤患者的治疗效果具有至关重要的临床意义。基于IDO1在促进肺肿瘤炎症性新血管生成中作用的临床前证据，本研究表明抑制IDO1引发的肿瘤内缺血应激如何增强缺血靶向药物的免疫原性细胞毒性，从而有效利用免疫检查点阻断反应性带来协同生存益处。这些发现为IDO1抑制剂如何影响肿瘤生物学提供了新视角，并为治疗应用开辟了新的可能性。
