Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses.
Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses.
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癌症中的多胺耗竭策略：重塑肿瘤免疫微环境以增强抗肿瘤反应。
DOI：
10.3390/medsci10020031
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发表时间：
2022-06-10
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多胺生物合成在癌症中经常失调，并且增强的通量增加促进细胞生长、增殖和功能所必需的细胞内多胺。多胺耗尽策略在癌症动物模型中证明了减少肿瘤生长和提高生存率的功效;然而，从机制上讲，肿瘤微环境中作为积极治疗结果基础的细胞内在和细胞外在改变尚不清楚。最近，研究人员已经证明，共同靶向多胺的生物合成和运输改变免疫景观。尽管靶向多胺合成的药物2-二氟甲基鸟氨酸（DFMO）在人体中耐受性良好，并且FDA批准用于非洲锥虫病，但其在治疗已确定癌症方面的临床益处尚未完全实现;然而，靶向代偿机制的联合疗法已在动物模型中显示出耐受性和有效性，目前正在临床试验中进行测试。如临床前模型所示，多胺阻断疗法（PBT）减少了肿瘤微环境中的免疫抑制，并增强了免疫检查点阻断（ICB）的治疗功效。因此，DFMO可以使肿瘤对其他治疗剂敏感，包括免疫治疗和化学治疗。
Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies.