Department of Mathematical and Statistical Sciences, University of Alberta, CAB 632, Edmonton, Alberta T6G 2G1, Canada.
J Theor Biol. 2019 Dec 7;482:109999. doi: 10.1016/j.jtbi.2019.109999. Epub 2019 Sep 4.
Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.
越来越多的实验和临床证据表明，免疫系统对癌症的反应不仅具有抗肿瘤作用。事实上，免疫系统的促肿瘤作用——例如作为生长和促血管生成因子的供应者，或抵御细胞毒性免疫攻击的防御者——早已被人们所认识，但相对较少的理论研究考虑到它们的影响。受最近提出的“免疫介导”转移理论的启发，我们开发了一个用于肿瘤-免疫相互作用的数学模型，该模型包括抗肿瘤和促肿瘤免疫效应，以及实验观察到的免疫细胞的肿瘤诱导表型可塑性（肿瘤对免疫细胞的“教育”）。当我们的模型与实验数据相对照时，我们用它来评估转移的免疫介导理论的含义。我们发现，免疫细胞的肿瘤教育可能解释了免疫疗法相对较差的效果，而且许多转移现象，包括转移爆发、休眠和转移到损伤部位，可以用转移的免疫介导理论来解释。我们的结果表明，有必要进一步研究以充分阐明免疫系统在转移性癌症中的促肿瘤作用。
