文章：

肿瘤免疫学小鼠模型

Mouse models in oncoimmunology

原文发布日期：2016-09-30

DOI: 10.1038/nrc.2016.91

类型: Review Article

开放获取: 否

要点：

1. The cell-autonomous conception of cancer has been progressively substituted by a view in which interactions of malignant and stromal elements, including immune cells, condition the tumour microenvironment.
2. Transplantable models of mouse cancers implanted in histocompatible, immunocompetent mice have spurred the development of immune checkpoint blockers, as well as the discovery that chemotherapy- and radiotherapy-induced immunogenic cell death stimulates therapeutically relevant anticancer immune responses.
3. Carcinogen-induced models have been instrumental for the discovery of the major principles of anticancer immunoediting, including elimination, equilibrium and escape.
4. Genetically engineered mouse models (GEMMs) are providing fundamental insights into tissue- and context-dependent mechanisms of immune recognition and suppression.
5. Modern genome-editing technologies offer the possibility of exchanging individual mouse genes or entire loci with their human equivalents with the possibility of introducing human elements of the immune and haematological systems into a progressively 'humanized' environment.
6. The combination of immunodeficiencies that affect the mouse immune system, the humanization of the mouse genome by knock in of human genes or loci and the transplantation of human immune cells and tumours provides ever more refined models for oncoimmunology.

要点翻译：

1. 癌症的细胞自主性概念已逐渐被一种新观点所取代，即恶性细胞与基质成分（包括免疫细胞）的相互作用塑造了肿瘤微环境。
2. 组织相容性免疫健全小鼠体内移植的鼠源癌症模型，不仅推动了免疫检查点阻断剂的研发，更揭示了化疗与放疗诱导的免疫原性细胞死亡能够激发具有治疗意义的抗癌免疫应答。
3. 致癌物诱导模型为发现抗癌免疫编辑的核心原理（清除-平衡-逃逸）提供了关键依据。
4. 基因工程小鼠模型正在揭示组织特异性与情境依赖性免疫识别及抑制机制的基础原理。
5. 现代基因组编辑技术不仅能够置换单个小鼠基因或完整基因座为人类同源序列，更可在逐步“人源化”的环境中引入人类免疫与血液系统要素。
6. 通过结合影响小鼠免疫系统的免疫缺陷、通过基因敲入实现小鼠基因组人源化，以及移植人类免疫细胞与肿瘤，最终为肿瘤免疫学构建出日益精细的研究模型。

英文摘要：

Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies — each with their specific advantages and difficulties — have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from immune control is an essential feature of cancer, the concept that the long-term effects of conventional cancer treatments mostly rely on the reinstatement of anticancer immune responses and the preclinical development of immunotherapies, including currently approved immune checkpoint blockers. Specific aspects of pharmacological development, as well as attempts to personalize cancer treatments using patient-derived xenografts, require the development of mouse models in which murine genes and cells are replaced with their human equivalents. Such 'humanized' mouse models are being progressively refined to characterize the leukocyte subpopulations that belong to the innate and acquired arms of the immune system as they infiltrate human cancers that are subjected to experimental therapies. We surmise that the ever-advancing refinement of murine preclinical models will accelerate the pace of therapeutic optimization in patients.

摘要翻译： 

基础癌症研究和有效抗肿瘤治疗的开发都依赖于能够研究恶性细胞与免疫细胞之间关系的实验系统。可移植、致癌物诱导或基因工程构建的小鼠肿瘤模型——各有其特定的优势和局限——奠定了肿瘤免疫学的基础。这些模型支持了免疫监视理论，即逃避免疫控制是癌症的基本特征；提出了常规癌症治疗的长期效果主要通过恢复抗癌免疫应答来实现的概念；并推动了免疫疗法的临床前开发，包括目前已获批的免疫检查点抑制剂。药物开发的特定方面，以及利用患者来源异种移植模型个性化癌症治疗的尝试，都需要建立将小鼠基因和细胞替换为其人类对应物的小鼠模型。这类“人源化”小鼠模型正被逐步优化，以表征属于先天性和获得性免疫系统的白细胞亚群如何浸润接受实验性治疗的人类肿瘤。我们推测，小鼠临床前模型的不断完善将加快患者治疗优化的步伐。

原文链接：

Mouse models in oncoimmunology