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Modeling LSD1-Mediated Tumor Stagnation
Bulletin of Mathematical Biology ( IF 3.5 ) Pub Date : 2021-01-12 , DOI: 10.1007/s11538-020-00842-8
Jesse Milzman 1 , Wanqiang Sheng 2 , Doron Levy 1
Affiliation  

LSD1 (KDMA1) has gained attention in the last decade as a cancer biomarker and drug target. In particular, recent work suggests that LSD1 inhibition alone reduces tumor growth, increases T cell tumor infiltration, and complements PD1/PDL1 checkpoint inhibitor therapy. In order to elucidate the immunogenic effects of LSD1 inhibition, we develop a mathematical model of tumor growth under the influence of the adaptive immune response. In particular, we investigate the anti-tumor cytotoxicity of LSD1-mediated T cell dynamics, in order to better understand the synergistic potential of LSD1 inhibition in combination immunotherapies, including checkpoint inhibitors. To that end, we formulate a non-spatial delay differential equation model and fit to the B16 mouse model data from Sheng et al. (Cell 174(3):549–563, 2018. https://doi.org/10.1016/j.cell.2018.05.052 ). Our results suggest that the immunogenic effect of LSD1 inhibition accelerates anti-tumor cytotoxicity. However, cytotoxicity does not seem to account for the slower growth observed in LSD1-inhibited tumors, despite evidence suggesting immune-mediation of this effect.

中文翻译:

建模 LSD1 介导的肿瘤停滞

LSD1 (KDMA1) 在过去十年中作为癌症生物标志物和药物靶点受到关注。特别是,最近的工作表明,单独的 LSD1 抑制可减少肿瘤生长,增加 T 细胞肿瘤浸润,并补充 PD1/PDL1 检查点抑制剂疗法。为了阐明 LSD1 抑制的免疫原性作用,我们开发了适应性免疫反应影响下肿瘤生长的数学模型。特别是,我们研究了 LSD1 介导的 T 细胞动力学的抗肿瘤细胞毒性,以更好地了解 LSD1 抑制在联合免疫疗法(包括检查点抑制剂)中的协同潜力。为此,我们制定了一个非空间延迟微分方程模型并拟合了盛等人的 B16 小鼠模型数据。(细胞 174(3):549–563,2018 年。https://doi.org/10.1016/j.cell.2018。05.052)。我们的结果表明,LSD1 抑制的免疫原性作用加速了抗肿瘤细胞毒性。然而,细胞毒性似乎并不能解释在 LSD1 抑制的肿瘤中观察到的缓慢生长,尽管有证据表明这种效应是免疫介导的。
更新日期:2021-01-12
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