Abstract
Neutrophils display rapid and potent innate immune responses in various diseases. Tumor-associated neutrophils (TANs) however either induce or overcome immunosuppressive functions of the tumor microenvironment through complex tumor-stroma crosstalk. We developed a mathematical model to address the question of how phenotypic alterations between tumor suppressive N1 TANS, and tumor promoting N2 TANs affect nonlinear tumor growth in a complex tumor microenvironment. The model provides a visual display of the complex behavior of populations of TANs and tumors in response to various TGF-β and IFN-β stimuli. In addition, the effect of anti-tumor drug administration is incorporated in the model in an effort to achieve optimal anti-tumor efficacy. The simulation results from the mathematical model were in good agreement with experimental data. We found that the N2-to-N1 ratio (N21R) index is positively correlated with aggressive tumor growth, suggesting that this may be a good prognostic factor. We also found that the antitumor efficacy increases when the relative ratio (Dap) of delayed apoptotic cell death of N1 and N2 TANs is either very small or relatively large, providing a basis for therapeutically targeting prometastatic N2 TANs.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide, with an approximate 1.6 million deaths each year [1]
It is well established that immune cells show functional plasticity in the context of cancer, and undergo phenotypic changes, promoting tumor growth and metastatic progression [74]
There have been substantial studies to pinpoint fundamental mechanisms through which Tumorassociated neutrophils (TANs) act on cancer progression [8, 17, 34], and especially via the coordination of chemotaxisdriven recruitment and activation of distinct immune cells to the tumor microenvironment [97,98,99,100] as well as immune suppression [74, 101, 102]
Summary
Lung cancer is the leading cause of cancer mortality worldwide, with an approximate 1.6 million deaths each year [1]. The most common (*85%) form of lung cancer in patients is nonsmall cell lung cancer (NSCLC), of which lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes [2]. Various groups of myeloid cells have been known to promote tumor development by direct inhibition of immune responses [3], as well as by secreting growth factors, angiogenic factors, or matrix-degrading enzymes [4, 5]. Tumor-associated macrophages (TAMs), known as M2 macrophages [3], have been shown to promote tumor growth [6, 7].
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