Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations.
Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations.
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DOI：
10.3390/cancers12123802
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发表时间：
2020-12-17
期刊：
影响因子：
5.2
通讯作者：
Najjar YG
中科院分区：
文献类型：
--
作者：
Augustin RC;Delgoffe GM;Najjar YG
几十年来，几乎所有的癌症患者都接受细胞毒性化疗，杀死体内任何快速分裂的细胞。最近，研究人员一直在研究免疫系统对癌症的反应，并开发出一类新型药物，刺激身体对肿瘤的反应。这类免疫治疗药物主要涉及T细胞，靶向和破坏癌细胞的免疫细胞。虽然这些药物可以导致显著和持续的反应，但大多数患者没有反应。了解无反应肿瘤的耐药机制现在是一个活跃的研究领域。在这篇综述中，我们探讨了肿瘤微环境中的一系列因素，肿瘤组织内的细胞和分子空间，以确定免疫治疗耐药性的可能罪魁祸首。具体而言，肿瘤微环境中低氧和代谢副产物的下游效应与免疫细胞功能障碍有关。重要的是，靶向这些途径可能提供有希望的疗法，以改善对当前免疫疗法的反应。免疫疗法（IMT）现在是癌症治疗的核心组成部分，然而，许多患者对这些新疗法没有反应。研究这种差异反应背后的抗性机制现在是一个关键的研究领域。基于免疫的疗法，特别是免疫检查点抑制剂（ICI），依赖于T细胞向肿瘤微环境（TME）中的稳健浸润以实现有效应答。虽然早期的努力依赖于定量TME中的肿瘤浸润淋巴细胞（TIL），但表征TIL耗竭的功能质量和程度与ICI反应更密切相关。即使有足够的TME浸润，免疫细胞也面临着可能显著损害效应子功能的恶劣代谢环境。这些肿瘤介导的代谢紊乱包括缺氧、氧化应激和细胞能量代谢物。缺氧首先通过HIF-1依赖性过程，通过改变分子标记物、免疫细胞运输和血管生成引起免疫抑制表型。此外，氧化应激可促进脂质过氧化、ER应激和Treg功能障碍，所有这些都与免疫失调相关。最后，脂质、氨基酸、葡萄糖和细胞能量的代谢副产物与免疫抑制和ICI抗性相关。本综述将探讨这些生化途径与免疫细胞功能障碍的TME和突出潜在的预防性治疗一起使用，目前的IMT。
For decades nearly all cancer patients were treated with cytotoxic chemotherapy, killing any rapidly dividing cell in the body. More recently, researchers have been studying the immune system’s response to cancer and have developed a novel class of drugs that stimulate the body’s own response to tumors. This class of immunotherapy drugs primarily involve T-cells, immune cells that target and destroy cancer cells. While these drugs can lead to remarkable and sustained response, most patients do not respond. Understanding the resistance mechanisms in non-responding tumors is now an active area of investigation. In this review, we explore a host of factors in the tumor microenvironment, the cellular and molecular space within tumor tissue, to identify possible culprits of immunotherapy resistance. Specifically, the downstream effects of low oxygen and metabolic byproducts in the tumor microenvironment have been associated with immune cell dysfunction. Importantly, targeting these pathways may offer promising therapies to improve the response to current immunotherapy. Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.
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影响因子：
37.3
作者：
Chang DK;Moniz RJ;Xu Z;Sun J;Signoretti S;Zhu Q;Marasco WA
通讯作者：
Marasco WA
影响因子：
11.2
作者：
Barsoum, Ivraym B.;Smallwood, Chelsea A.;Graham, Charles H.
通讯作者：
Graham, Charles H.
影响因子：
45.3
作者：
Borad, Mitesh J.;Reddy, Shantan G.;Ryan, David P.
通讯作者：
Ryan, David P.
影响因子：
8.8
作者：
Benjamin, Don;Robay, Dimitri;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Bettigole SE;Glimcher LH
通讯作者：
Glimcher LH