Bistable dynamics of TAN-NK cells in tumor growth and control of radiotherapy-induced neutropenia in lung cancer treatment.

Neutrophils play a crucial role in the innate immune response as a first line of defense in many diseases, including cancer. Tumor-associated neutrophils (TANs) can either promote or inhibit tumor growth in various steps of cancer progression via mutual interactions with cancer cells in a complex tumor microenvironment (TME). In this study, we developed and analyzed mathematical models to investigate the role of natural killer cells (NK cells) and the dynamic transition between N1 and N2 TAN phenotypes in killing cancer cells through key signaling networks and how adjuvant therapy with radiation can be used in combination to increase anti-tumor efficacy. We examined the complex immune-tumor dynamics among N1/N2 TANs, NK cells, and tumor cells, communicating through key extracellular mediators (Transforming growth factor (TGF-$ \beta $), Interferon gamma (IFN-$ \gamma $)) and intracellular regulation in the apoptosis signaling network. We developed several tumor prevention strategies to eradicate tumors, including combination (IFN-$ \gamma $, exogenous NK, TGF-$ \beta $ inhibitor) therapy and optimally-controlled ionizing radiation in a complex TME. Using this model, we investigated the fundamental mechanism of radiation-induced changes in the TME and the impact of internal and external immune composition on the tumor cell fate and their response to different treatment schedules.