Neutrophils In Tumor Microenvironment Research Articles

Versatility of neutrophils in tumor microenvironment

Versatility of neutrophils in tumor microenvironment

Abstract 6289: Activated neutrophils induce robust mesenchymal migration of gastric cancer cells

Abstract Background: Activated neutrophils can produce multiple substances including various enzymes such as neutrophil elastase, myeloperoxidase, as well as many cytokines and reactive oxygen species (ROS). In addition, in some circumstances, they produce neutrophil extracellular traps (NETs), which is unfolded DNA fibers showing such a web-like structure containing histone and various proteins. However, recent studies have suggested NETs can promote tumor metastasis. In fact, many neutrophils are infiltrating in tumor tissues which are called tumor associated neutrophils (TAN) and high TANs are associated with poor prognosis. However, the detailed effects of TAN on tumor cell behavior are still not fully understood. Methods: Human peripheral polymorph neutrophils (PMN) collected from healthy donor were stimulated with 1μM PMA or 10μg/ml LPS for 15 min, washed extensively, and incubated for another 3 hours. Using trans-well system with culture inserts with 8μm pore membrane, we examined the migration of human gastric cancer cells NUGC-4 or MKN45 to 2% FBS placed in lower chamber with or without PMN. Random migration was also examined with time-lapsed analysis. Lamellipodia were detected with F-actin stained with phalloidin-488 and immunostaining to vinculin. Results: PMN stimulated with either PMA or LPS produced large amounts of NETs stained with SYTOX. NUGC-4 and MKN45 showed little migration to unstimulated PMN, while many cells did migrate when PMA-activated PMN were present in lower chamber. Although NET-depleted supernatants (SN) also induced significant migration, the number of migrated cells was reduced to about 50%. When catalase (800U/ml) catalase was added, the migrations of NUGC-4 was significantly reduced (37%). Random migration was markedly enhanced by NET-depleted SN. Addition of the SN induced many lamellipodia in NUGC-4 within 30 min. The migration of NUGC-4 was also increased by PMN stimulated by LPS, but not by their NET-depleted SN. Summary and Conclusion: PMA-stimulated neutrophils induce robust migration of cancer cells which is partly dependent on H2O2. LPS-stimulated neutrophils appear to produce less amounts of ROS, but can also enhance the NUGC-4 migration through NET dependent manner. Activated neutrophils in tumor microenvironment can stimulate migration of cancer cells through multiple mechanisms, and assist the initial step of metastatic process of primary tumor. Citation Format: Kazuya Takahashi, Hideyuki Ohzawa, Yuki Kaneko, Yurie Futoh, Kohei Tamura, Yuki Kimura, Akira Saito, Mineyuki Tojo, Rihito Kanamaru, Hideyo Miyato, Naohiro Sata, Joji Kitayama. Activated neutrophils induce robust mesenchymal migration of gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6289.

Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.

Neutrophils are the first defenders of the innate system for injury and infection. They have gradually been recognized as important participants in tumor initiation and development due to their heterogeneity and plasticity. In the tumor microenvironment (TME), neutrophils can exert antitumor and protumor functions, depending on the surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms that determine how altered AAs affect neutrophils in TME are less‐explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils’ cell‐killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, flow cytometry, and western blot experiments proved that increased levels of pSTAT3/RAB10/ARF4, mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that riluzole, an FDA‐approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils’ cell‐killing effects and decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor‐released glutamate on neutrophil transformation in TME, providing new possible cancer treatments targeting altered glutamate metabolism.

Polymorphonuclear Neutrophils and Tumors: Friend or Foe?

Tumor microenvironment (TME) is a dynamic network that apart from tumor cells includes also cells of the immune system, e.g., neutrophils, which are recruited from blood circulation. In TME, neutrophils are strongly implicated in the direct and indirect interactions with tumor cells or other immune cells, and they play roles in both preventing and/or facilitating tumor progression and metastasis. The dual role of neutrophils is determined by their high plasticity and heterogeneity. Analogous to the macrophages, neutrophils can express antitumoral (N1) and protumoral (N2) phenotypes which differ substantially in morphology and function. N1 phenotype characterizes with a high cytotoxic and proinflammatory activities, while N2 phenotype with immunosuppressive and prometastatic properties. The antitumoral effect of neutrophils includes for example the production of reactive oxygen species or proapoptotic molecules. The protumoral action of neutrophils relies on releasing of proangiogenic and prometastatic mediators, immunosuppressive factors, as well as on direct helping tumor cells in extravasation process. This chapter summarizes the heterogeneity of neutrophils in TME, as well as their dual role on tumor cells.

Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma

BackgroundNeutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate...

Function and interaction between macrophages and neutrophils in tumor microenvironment

肿瘤微环境（tumor microenvironment，TME）与肿瘤的生存和发展密切相关。在TME中，巨噬细胞和中性粒细胞均具有促进肿瘤进展和转移的作用，且两者之间可能存在不同程度的相互作用。目前，越来越多的研究证实，肿瘤的发生与发展不仅是肿瘤细胞的基因突变所致，还与突变细胞对TME的适应过程有关。在临床实践中，开发出能同时靶向肿瘤细胞和TME的新治疗策略，将会为肿瘤的治疗指明新的方向。.

Tumor-promoting effect of IL-23 in mammary cancer mediated by infiltration of M2 macrophages and neutrophils in tumor microenvironment

Interleukin 23 (IL-23) is an inflammatory cytokine which plays a vital role in autoimmune diseases as well as in tumorigenesis. However, the role of IL-23 in tumor procession is still controversial and the underlying mechanism remains unclear. Here we established a stable cell line overexpressing IL-23 to prove that IL-23 promoted tumor growth and pulmonary metastasis through induction of tumor-related inflammation and absence of immune surveillance. IL-23 promotes tumor-associate inflammatory response such as infiltration of M2 macrophages, neutrophils and their elevated secretions of immunosuppressive cytokines transforming growth factor-β (TGF-β), IL-10 and vascular endothelial growth factor (VEGF) into tumor tissues, meanwhile the increase of the matrix metalloprotease MMP9. In addition, IL-23 increases the expression of the endothelial marker CD31 and proliferative marker Ki67 in tumors. Moreover, IL23 induces immunosuppression though reducing the infiltration of CD4+and CD8+T cells into tumor tissues. In conclusion, IL-23 is a considerable molecular in tumor progression, which simultaneously facilitates processes of pro-tumor inflammation, such as angiogenesis, immunosuppressive cytokines as well as infiltrations of M2 macrophages and neutrophils, and suppresses antitumor immune responses through reduction of CD4+ T cells and CD8+ T cells.

Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment.

Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor-associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor-associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor-associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors.

Prognostic value of neutrophil distribution in cholangiocarcinoma.

To explore the relationship of clinicopathological features and the distribution of neutrophils in the tumor microenvironment with the prognosis of cholangiocarcinoma. Two hundred and fifty-four formalin-fixed and paraffin embedded tissue blocks were analyzed, including tissues from cholangiocarcinoma (n = 254), and tumor adjacent tissues (n = 238). Tissue sections were stained for CD15 using immunohistochemical staining. CD15 expression was detected to identify the distribution of neutrophils in the local tumor microenvironment. The neutrophil density of the tumor tissues and the adjacent tumor tissues was detected to reflect their inflammatory status. Clinical data and follow-up information of cholangiocarcinoma patients who underwent surgery from January 2004 to December 2010 were analyzed retrospectively. The relationship between clinicopathological features and the distribution of neutrophils with prognosis of the patients were analyzed. The positive expression level of CD15 was only significantly related to the TNM stage. CD15 expression was higher in tumor tissues than in adjacent tissues (73.6% vs 54.6%), with significant differences. Patients with high expression of CD15 had significantly shorter overall survival (OS) than those with low expression of CD15 (median overall survival time 39.77 mo vs 16.87 mo, P = 0.008). Patients with high CD15 expression had significantly shorter disease free survival time (DFS) than those with low expression of CD15 (median DFS 38.27 mo vs 16.83 mo, P = 0.029). COX multivariate analysis indicated that high CD15 expression in tumor tissues was an independent risk factor for predicting OS for patients with cholangiocarcinoma [P = 0.012, relative risk (RR) = 1.601], but it was not an independent risk factor for predicting DFS (P = 0.073, RR = 1.462). Patients with high CD15 expression in cancer tissues had shorter DFS and OS. High expression of CD15 is an independent risk factor for OS.