T 淋巴细胞抑制永久性休眠中自发转移。
T lymphocytes restrain spontaneous metastases in permanent dormancy.
机构信息
Authors' Affiliations: Dept. Analisis Clinicos e Inmunologia, UGC Laboratorio Clínico; Unidad de Investigación, Hospital Universitario Virgen de las Nieves, Granada; Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada; and Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain.
出版信息
Cancer Res. 2014 Apr 1;74(7):1958-68. doi: 10.1158/0008-5472.CAN-13-2084. Epub 2014 Feb 14.
Tumor dormancy is a clinical phenomenon related to immune equilibrium during cancer immunoediting. The mechanisms involved in dormant metastases are poorly understood due to the lack of preclinical models. Here, we present a nontransgenic mouse model in which spontaneous metastases remain in permanent immunomediated dormancy with no additional antitumor treatment. After the injection of a GR9-B11 mouse fibrosarcoma clone into syngeneic BALB/c mice, all animals remained free of spontaneous metastases at the experimental endpoints (3-8 months) but also as long as 24 months after tumor cell injection. Strikingly, when tumor-bearing mice were immunodepleted of T lymphocytes or asialo GM1-positive cells, the restraint on dormant disseminated metastatic cells was relieved and lung metastases progressed. Immunostimulation was documented at both local and systemic levels, with results supporting the evidence that the immune system was able to restrain spontaneous metastases in permanent dormancy. Notably, the GR9-B11 tumor clone did not express MHC class I molecules on the cell surface, yet all metastases in immunodepleted mice were MHC class I-positive. This model system may be valuable for more in-depth analyses of metastatic dormancy, offering new opportunities for immunotherapeutic management of metastatic disease.
肿瘤休眠是与癌症免疫编辑过程中的免疫平衡相关的一种临床现象。由于缺乏临床前模型,因此对于休眠转移涉及的机制了解甚少。在这里,我们提出了一种非转基因小鼠模型,其中自发转移在没有任何额外抗肿瘤治疗的情况下保持永久的免疫介导休眠。将 GR9-B11 小鼠纤维肉瘤克隆注入同基因 BALB/c 小鼠后,所有动物在实验终点(3-8 个月)时均未发生自发转移,并且在肿瘤细胞注射后长达 24 个月也未发生转移。引人注目的是,当荷瘤小鼠的 T 淋巴细胞或去唾液酸 GM1 阳性细胞被免疫耗竭时,对休眠性播散转移细胞的抑制作用被解除,肺转移进展。在局部和全身水平都记录到了免疫刺激,结果支持了免疫系统能够将自发转移在永久休眠中抑制的证据。值得注意的是,GR9-B11 肿瘤克隆在细胞表面不表达 MHC Ⅰ类分子,但免疫耗竭小鼠中的所有转移均为 MHC Ⅰ类阳性。该模型系统可能对休眠转移的更深入分析具有重要价值,为转移性疾病的免疫治疗管理提供了新的机会。