Abstract 7261: Dynamical mathematical models reveal that cell cycle inhibitors promote immunogenicity and T cell cytotoxicity when combined with IL-15 in estrogen receptor positive breast cancer cell lines
Authors: Jiyeon Park, Frederick R. Adler, Aritro Nath, Jason I. Griffiths, Patrick A. Cosgrove, Kimya Karimi
Journal: Cancer Research (2025)

Abstract Advanced estrogen receptor positive (ER+) breast cancers are typically treated with endocrine therapy (ET) plus cell cycle inhibitors (CCI); however, nearly 20% of these cancers recur due to treatment resistance. Our previous study of tumor intrinsic properties during CCI plus ET treatment found that CCI-resistant cancer cells are associated with diminished immune-activating signals to cytotoxic CD8+ T cells due in part to reduced interleukin-15 (IL-15) signaling, a potent immunostimulatory cytokine. This finding motivates our study of combination IL-15/T-cell based immune-activating treatment regimen development. However, the fact that CCI also inhibit immune cells challenges this immunotherapy development, creating complex interactions that require mathematical modeling in collaboration with in vivo experiments to analyze. To study these complex interactions, we develop a nonlinear ordinary differential equation mathematical model that describes the tumor ecosystem of interacting cancer cells and cytotoxic T cells linked with pharmacokinetics of ribociclib (CCI) and IL-15. We design experimental model using 3D spheroids of CCI-sensitive and resistant cancer cell lines in monoculture or co-cultured with patient-derived cytotoxic T cells and tracked over 5 days of growth. These spheroids were treated with CCI alone or in combination with IL-15. This dynamical model accurately fits experimental data by quantifying the effects of both treatments on the growth rates and interactions between cancers and T cells. Key parameters of our model quantify how treatments impact the promotion of T cell recruitment and T cell activation by cancer cell antigens. These combine to lead to the subsequent killing of cancer cells. Analyzing these parameters under various dose drug combinations drives to three main findings: (1) proliferation of both cell types are suppressed by CCI, while only T cells are activated by IL-15, (2) CCI, despite slowing T cell proliferation, promote immunogenicity and immune cell toxicity in combination with IL-15, and (3) the enhanced immune capacity under this combination treatment is higher in ribociclib-resistant cancer cell lines than in sensitive cell lines. The mathematical modeling reveals that combining immune-activating treatment (IL-15) with a cell cycle inhibitor (ribociclib) outperforms single therapy in limiting cancer cell growth. Furthermore, cancer cells resistant to cell cycle inhibitors are more effectively targeted by this combination therapy. For future work, we will use the mathematical model to propose optimal therapy regimens that minimize the total dosage of the two drugs and maximize treatment response with long-term goal of overcoming recurrence due to drug resistance by strengthening immune surveillance in ER+ breast cancers. Citation Format: Jiyeon Park, Frederick R. Adler, Aritro Nath, Jason I. Griffiths, Patrick A. Cosgrove, Kimya Karimi. Dynamical mathematical models reveal that cell cycle inhibitors promote immunogenicity and T cell cytotoxicity when combined with IL-15 in estrogen receptor positive breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7261.