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Modeling LSD1-Mediated Tumor Stagnation
Jesse Milzman1, Wanqiang Sheng2, Doron Levy3
1Department of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM), University of Maryland, College Park, MD, 20742, USA. jmilzman@umd.edu.
Abstract:
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.
Insights
Lysine-specific demethylase 1 (LSD1) inhibition boosts anti-tumor T cell activity. Mathematical modeling reveals accelerated cytotoxicity but suggests it doesn't fully explain slower tumor growth in combination immunotherapies.
Area of Science:
- Immunology
- Computational Biology
- Oncology
Background:
- Lysine-specific demethylase 1 (LSD1) is recognized as a cancer biomarker and therapeutic target.
- LSD1 inhibition shows promise in reducing tumor growth and enhancing T cell infiltration.
- LSD1 inhibition may synergize with PD1/PDL1 checkpoint inhibitors in cancer immunotherapy.
Purpose of the Study:
- To elucidate the immunogenic effects of LSD1 inhibition on tumor growth and adaptive immune response.
- To investigate the anti-tumor cytotoxicity mediated by LSD1 inhibition and T cell dynamics.
- To understand the synergistic potential of LSD1 inhibition in combination immunotherapies.
Main Methods:
- Development of a non-spatial delay differential equation mathematical model.
- Modeling of tumor growth influenced by the adaptive immune response.
- Fitting the model to data from the B16 mouse model (Sheng et al., 2018).
Main Results:
- LSD1 inhibition accelerates anti-tumor cytotoxicity.
- Cytotoxicity alone does not fully account for the observed slower tumor growth under LSD1 inhibition.
- Evidence suggests immune mediation of the slower tumor growth effect.
Conclusions:
- LSD1 inhibition enhances the immune system's ability to fight cancer.
- Further research is needed to reconcile the accelerated cytotoxicity with the slower tumor growth.
- Mathematical modeling provides insights into the complex interplay between LSD1 inhibition and anti-tumor immunity.
