Research Article: Role of tumor-associated neutrophils in regulation of tumor growth in lung cancer development: A mathematical model

Date Published: January 28, 2019

Publisher: Public Library of Science

Author(s): Yangjin Kim, Donggu Lee, Junho Lee, Seongwon Lee, Sean Lawler, Eugene Demidenko.


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.

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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 non-small 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]. For example, tumor-associated macrophages (TAMs), also known as M2 macrophages [3], have been shown to promote tumor growth [6, 7]. There is growing evidence suggesting that neutrophils play a major role in tumor progression from establishment of tumor formation and throughout the progression to the malignant state [8–12]. For example, tumor associated neutrophils (TANs) have been associated with poor prognosis in many cancers including metastatic melanoma [13], bronchoalveolar carcinoma [14], and renal carcinoma [15]. Like TAMs, TANs infiltrate tumor tissue and can have two differential states in cancer progression [8, 9, 16]: (i) an antitumorigenic role (called N1) (ii) promoting tumor progression (called N2). How these two phenotypes are regulated is largely unknown but many experimental and clinical findings suggest the significant potential of therapeutic targeting of the prometastatic role of TANs [17].

The immune system protects the host against various types of biological threats. However, 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 TANs act on cancer progression [8, 17, 34], and especially via the coordination of chemotaxis-driven recruitment and activation of distinct immune cells to the tumor microenvironment [97–100] as well as immune suppression [74, 101, 102]. A groundbreaking work by Fridlender and colleagues [16] had illustrated that TGF-β in tumor microenvironment can generate a functional transition from the proinflammatory neutrophil phenotype (termed “N1”) to the anti-inflammatory phenotype (termed “N2”); [74]. IL-6 also contributes to the formation of the N2 microenvironment [103, 104]. Neutrophil-to-lymphocyte ratio (NLR) was highly associated with progression in many cancer types [69] and has been suggested to be a prognostic factor (or biomarker) for various cancers including colorectal cancer [105, 106], nasopharyngeal carcinoma [107], non-small-cell lung cancer [71], breast cancer [108, 109], hepatocellular carcinoma [110], and melanoma [13]. Recently, it was shown that lung adenocarcinomas can promote bone stromal activity and increase bone mass even without bone metastasis, which in turn enhances tumor growth by remotely supplying tumor-infiltrating neutrophils [111]. However, how the systemic host environment can communicate with a tumor at a remote site is poorly understood.




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