肿瘤外 IDO1 靶点结合决定癌症免疫基准点，并预测免疫治疗疗效。
Off-tumor IDO1 target engagements determine the cancer-immune set point and predict the immunotherapeutic efficacy.
机构信息
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
出版信息
J Immunother Cancer. 2021 Jun;9(6). doi: 10.1136/jitc-2021-002616.
BACKGROUND
Indoleamine-2,3-dioxygenase 1 (IDO1) has been intensively pursued as a therapeutic target to reverse the immunosuppressive cancer-immune milieu and promote tumor elimination. However, recent failures of phase III clinical trials with IDO1 inhibitors involved in cancer immunotherapies highlight the urgent need to develop appropriate methods for tracking IDO1 when the cancer-immune milieu is therapeutically modified.
METHODS
We utilized a small-molecule radiotracer, C-l-1MTrp, to quantitatively and longitudinally visualize whole-body IDO1 dynamics. Specifically, we first assessed C-l-1MTrp in mice-bearing contralateral human tumors with distinct IDO1 expression patterns. Then, we applied C-l-1MTrp to longitudinally monitor whole-body IDO1 variations in immunocompetent melanoma-bearing mice treated with 1-methyl-l-tryptophan plus either chemotherapeutic drugs or antibodies targeting programmedcell death 1 and cytotoxic T-lymphocyte-associated protein 4.
RESULTS
C-l-1MTrp positron emission tomography (PET) imaging accurately delineated IDO1 expression in xenograft mouse models. Moreover, we were able to visualize dynamic IDO1 regulation in the mesenteric lymph nodes (MLNs), an off-tumor IDO1 target, where the percentage uptake of C-l-1MTrp accurately annotated the therapeutic efficacy of multiple combination immunotherapies in preclinical models. Remarkably, C-l-1MTrp signal intensity in the MLNs was inversely related to the specific growth rates of treated tumors, suggesting that IDO1 expression in the MLNs can serve as a new biomarker of the cancer-immune set point.
CONCLUSIONS
PET imaging of IDO1 with C-l-1MTrp is a robust method to assess the therapeutic efficacy of multiple combinatorial immunotherapies, improving our understanding of the merit and challenges of IDO1 regimens. Further validation of this animal data in humans is ongoing. We envision that our results will provide a potential precision medicine paradigm for noninvasive visualizing each patient's individual response in combinatorial cancer immunotherapy, and tailoring optimal personalized combination strategies.
背景
吲哚胺 2,3-双加氧酶 1（IDO1）已被广泛研究作为一种治疗靶点，以逆转免疫抑制性的肿瘤免疫微环境并促进肿瘤消除。然而，最近癌症免疫疗法中 IDO1 抑制剂的 III 期临床试验失败突显了迫切需要开发适当的方法来跟踪癌症免疫微环境治疗性修饰时的 IDO1。
方法
我们利用小分子示踪剂 C-l-1MTrp 来定量和纵向可视化全身 IDO1 动力学。具体来说，我们首先在具有不同 IDO1 表达模式的对侧人肿瘤的小鼠模型中评估了 C-l-1MTrp。然后，我们应用 C-l-1MTrp 来纵向监测免疫功能正常的黑色素瘤荷瘤小鼠全身 IDO1 的变化，这些小鼠接受了 1-甲基-L-色氨酸联合化疗药物或靶向程序性细胞死亡 1 和细胞毒性 T 淋巴细胞相关蛋白 4 的抗体治疗。
结果
C-l-1MTrp 正电子发射断层扫描（PET）成像准确描绘了异种移植小鼠模型中的 IDO1 表达。此外，我们能够在肠系膜淋巴结（MLNs）中观察到 IDO1 的动态调节，这是一个肿瘤外的 IDO1 靶点，其中 C-l-1MTrp 的摄取百分比准确注释了多种组合免疫疗法在临床前模型中的治疗效果。值得注意的是，MLNs 中的 C-l-1MTrp 信号强度与治疗肿瘤的特定生长率呈负相关，这表明 MLNs 中的 IDO1 表达可以作为癌症免疫设定点的新生物标志物。
结论
使用 C-l-1MTrp 进行 IDO1 的 PET 成像，是评估多种组合免疫疗法治疗效果的强大方法，加深了我们对 IDO1 方案的优势和挑战的理解。目前正在对这些动物数据进行人体验证。我们设想，我们的结果将为非侵入性可视化每个患者在组合癌症免疫疗法中的个体反应并定制最佳个性化组合策略提供潜在的精准医学范例。
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