Modeling LSD1-Mediated Tumor Stagnation
Modeling LSD1-Mediated Tumor Stagnation
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DOI：
10.1007/s11538-020-00842-8
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发表时间：
2021-01-12
影响因子：
3.5
通讯作者：
Levy, Doron
中科院分区：
文献类型：
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作者：
Milzman, Jesse;Sheng, Wanqiang;Levy, Doron
LSD 1（KDMA 1）在过去十年中作为癌症生物标志物和药物靶标受到关注。特别是，最近的研究表明，单独抑制LSD 1可以减少肿瘤生长，增加T细胞肿瘤浸润，并补充PD 1/PDL 1检查点抑制剂治疗。为了阐明LSD 1抑制的免疫原性效应，我们开发了适应性免疫应答影响下肿瘤生长的数学模型。特别是，我们研究了LSD 1介导的T细胞动力学的抗肿瘤细胞毒性，以便更好地了解LSD 1抑制在联合免疫治疗（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Sheng等人的B16小鼠模型数据（Cell 174（3）：549-563，2018）。).我们的结果表明，LSD 1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LSD 1抑制肿瘤中观察到的生长较慢，尽管有证据表明这种效应的免疫介导。
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. ). 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.