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

PLOS ONE, Jan 2019

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

January Role of tumor-associated neutrophils in regulation of tumor growth in lung cancer development: A mathematical model Yangjin KimID 0 1 Donggu Lee 0 1 Junho Lee 0 1 Seongwon Lee 1 Sean Lawler 1 0 Department of Mathematics, Konkuk University , Seoul , Republic of Korea, 2 Mathematical Biosciences Institute, Ohio State University , Columbus , Ohio, United States of America, 3 Division of Mathematical Models, National Institute for Mathematical Sciences, Daejeon, Republic of Korea, 4 Department of neurosurgery, Harvard Medical School & Brigham and Women's Hospital , Boston, Massachusetts , United States of America 1 Editor: Eugene Demidenko, Dartmouth College Geisel School of Medicine , UNITED STATES Neutrophils display rapid and potent innate immune responses in various diseases. Tumorassociated 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-? and IFN-? 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. - Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. Funding: This work was supported by Konkuk University 2015 Research fund (www.konkuk.ac. kr, Y.J.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction 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 ]. 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 ]. TGF-? has been identified as a major cytokine within a tumor that skews neutrophil differentiation toward the N2 phenotype [ 16, 18, 19 ], while TGF-? blockade and type-1 IFN (?, ?, ?) treatment are known to shift the balance toward the N1 phenotype [ 20, 21 ]. IFN-? in tumor microenvironment can directly suppress tumor growth [22] by interacting with p53 [ 23?25 ]. IFN treated neutrophils were shown to upregulate PD-L1 and suppress T-cell proliferation [ 26 ]. After binding to interferon receptor type 1, IFNAR1 and IFNAR2, Type 1 IFN-? signals through TYK2 and JAK1, which in turn phosphorylate STAT family members (STAT1, STAT2, STAT3, and others) and activate its downstream functions to stimulate anti-tumor activities [ 27 ]. For example, vesicular stomatitis virus expressing IFN-? was shown to enhance anti-tumor immune responses in a murine model of NSCLC [ 28 ]. It is well established that cancer associated fibroblasts (CAFs) can promote tumor growth, aggressive invasion, and metastasis through mutual interaction in the tumor microenvironment [ 29, 30 ]. Fibrob (...truncated)


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Yangjin Kim, Donggu Lee, Junho Lee, Seongwon Lee, Sean Lawler. Role of tumor-associated neutrophils in regulation of tumor growth in lung cancer development: A mathematical model, PLOS ONE, 2019, Volume 14, Issue 1, DOI: 10.1371/journal.pone.0211041