文章：

靶向肿瘤免疫耐受机制的小分子抑制剂

Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors

原文发布日期：2006-08-01

DOI: 10.1038/nrc1929

类型: Review Article

开放获取: 否

要点：

1. Tumours dominantly suppress anti-tumour immunity through various pro-toleragenic mechanisms. A particularly attractive approach to target these mechanisms might be through the development of small-molecule immunotherapeutic drugs.
2. The indoleamine 2,3-dioxygenase (IDO) enzyme, which catabolizes the essential amino acid tryptophan, promotes tumoral immune tolerance by blocking the activation of effector T cells. Cancer cells express IDO, as do antigen-presenting dendritic cells that are present in tumour-draining lymph nodes, and both might contribute to immune escape. A small-molecule IDO inhibitor is in preclinical development.
3. The arginase (ARG)1 enzyme, which is expressed by tumour cells, myeloid suppressor cells and tumour-associated macrophages, has been implicated in suppressing anti-tumour immunity through catabolism of the amino acid arginine. Inducible nitric-oxide synthase (iNOS), another enzyme that catabolizes arginine, generally shows reciprocal regulation to ARG. However, in the context of some tumours, increased expression of both enzymes might contribute to immune suppression. Nitroaspirin, which inhibits both enzymes, is currently the most promising small molecule in development.
4. The cyclooxygenase 2 (COX2) enzyme has a central role in regulating the mechanisms of immune suppression and promotes the generation of regulatory T cells. Selective COX2 inhibitors have demonstrated evidence of additional clinical benefit in combination with chemotherapeutic agents, but recent concerns over safety have slowed testing. Inhibitors that target the prostaglandin receptors might represent an alternative.
5. The transforming growth factor β (TGFβ) cytokine can have profound immunosuppressive effects, and cancer cells adapt by becoming refractory to TGFβ signalling. Several approaches aimed at inhibiting TGFβ signalling are currently being investigated in terms of therapeutic potential, including small-molecule inhibitors of the TGFβ receptor tyrosine kinase.
6. Targeting downstream Janus kinase (JAK)–signal-tansducer-and-activator-of-transcription (STAT) signalling pathways might be an option for interfering with toleragenic cytokine activity, as might the vascular-endothelial-growth-factor (VEGF) receptor FMS-related tyrosine kinase 1 (FLT1), which can promote defective dendritic-cell maturation. Chemokines have also been implicated in the recruitment of immunosuppressive effector cell types to the local tumour microenvironment. Small-molecule inhibitors of the chemokine receptors CCR4, CXCR4 and CCR2 are currently in preclinical development.
7. One potential application of anti-toleragenic, small-molecule immunotherapeutics might be in combination with standard cytotoxic chemotherapies. The possibility that these new agents might improve standard treatments should facilitate clinical testing.

要点翻译：

1. 肿瘤主要通过多种致耐受机制来显性抑制抗肿瘤免疫。靶向这些机制的一个特别有吸引力的方法可能是开发小分子免疫治疗药物。
2. 吲哚胺2,3-双加氧酶（IDO）能催化必需氨基酸色氨酸的分解，通过阻断效应T细胞的活化来促进肿瘤免疫耐受。癌细胞以及肿瘤引流淋巴结中的抗原呈递树突状细胞均表达IDO，两者都可能促进免疫逃逸。一种小分子IDO抑制剂正处于临床前开发阶段。
3. 由肿瘤细胞、髓系抑制性细胞和肿瘤相关巨噬细胞表达的精氨酸酶（ARG）1，通过催化分解精氨酸参与抑制抗肿瘤免疫。另一催化精氨酸分解的酶——诱导型一氧化氮合酶（iNOS），通常表现出与ARG的相互调节作用。然而，在某些肿瘤中，这两种酶的表达增加可能共同导致免疫抑制。能同时抑制这两种酶的硝基阿司匹林是目前最有开发前景的小分子。
4. 环氧合酶2（COX2）在免疫抑制机制的调节中起核心作用，并促进调节性T细胞的生成。选择性COX2抑制剂与化疗药物联用已显示出额外的临床获益证据，但近期对其安全性的担忧减缓了相关试验。靶向前列腺素受体的抑制剂可能是一种替代方案。
5. 转化生长因子β（TGFβ）细胞因子具有深远的免疫抑制效应，而癌细胞通过变得对TGFβ信号不敏感来适应。目前正在从治疗潜力角度研究几种旨在抑制TGFβ信号的方法，包括TGFβ受体酪氨酸激酶的小分子抑制剂。
6. 靶向下游Janus激酶（JAK）-信号转导与转录激活因子（STAT）信号通路，以及可能促进树突状细胞缺陷性成熟的血管内皮生长因子（VEGF）受体FMS相关酪氨酸激酶1（FLT1），或许是干扰致耐受性细胞因子活性的可选策略。趋化因子也参与将免疫抑制性效应细胞类型招募至局部肿瘤微环境。针对趋化因子受体CCR4、CXCR4和CCR2的小分子抑制剂目前正处于临床前开发阶段。
7. 抗致耐受性小分子免疫治疗药物的一种潜在应用可能是与标准细胞毒性化疗联用。这些新药有望改进标准治疗方案，这将推动其临床测试的开展。

英文摘要：

Cancer immunotherapy has been predominantly focused on biologically based intervention strategies. However, recent advances in the understanding of tumour–host interactions at the molecular level have revealed targets that might be amenable to intervention with small-molecule inhibitors. In particular, key effectors of tumoral immune escape have been identified that contribute to a dominant toleragenic state that is suspected of limiting the successful implementation of treatment strategies that rely on boosting immune function. Within the context of the pathophysiology of cancer-associated immune tolerance, this Review delineates potential molecular targets for therapeutic intervention and the progress that has been made in developing small-molecule inhibitors.

摘要翻译： 

癌症免疫治疗主要集中于基于生物学的干预策略。然而，最近在分子水平上对肿瘤与宿主相互作用的研究进展揭示了一些可能适合用小分子抑制剂进行干预的靶点。特别是，已经识别出肿瘤免疫逃逸的关键效应因子，这些因子促成了一种占主导地位的耐受状态，这种状态被认为限制了依赖增强免疫功能的治疗策略的成功实施。在癌症相关免疫耐受的病理生理背景下，本综述阐述了潜在的治疗干预分子靶点，以及在小分子抑制剂开发方面取得的进展。

原文链接：

Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors