Human neutrophils depend on extrinsic factors produced by monocytes for their survival response to TLR4 stimulation

SenGupta, Shuvasree; Rane, Madhavi J.; Uriarte, Silvia M.; Woolley, Cassandra; Mitchell, Thomas C.

doi:10.1177/1753425919871994

Cited by 5 publications

(7 citation statements)

References 48 publications

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“…Neutrophils have very short life spans, however recent studies point to the role of pro-inflammatory soluble mediators in extending neutrophil survival (64,91). Indeed, many of the soluble factors including CXCL8, G-CSF, and GM-CSF, secreted abundantly from the M4 and MDA-MB-231metastatic breast cancer cells, are known to have pro-survival effect on neutrophils (64,91). Hence, we envisage that the prosurvival effect of M4 secreted factors also underlie the persistence of more neutrophils near M4 spheroids.…”

Section: Discussionmentioning

confidence: 99%

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Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands

SenGupta

Hein

et al. 2021

Front. Immunol.

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Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO (CXCL1/2/3) chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.

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Section: Discussionmentioning

confidence: 99%

“…One of the major signaling pathways triggered in neutrophils by a wide range of activating factors, including chemoattractants, is the extracellular signal-regulated kinase (ERK) pathway (63,64).…”

Section: Tnbc Cell Lines Secrete Neutrophil Activating Factors More Abundantly Than Er+ Cancer Cell Linesmentioning

confidence: 99%

Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands

SenGupta

Hein

et al. 2021

Front. Immunol.

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“…Additionally, CXCL5 and 7 released from tumor-activated platelets were reported to be crucial for neutrophil recruitment to the pre-metastatic niche and subsequent tumor cell seeding in the mouse lung (26). G-CSF and GM-CSF are important growth factors commonly upregulated in cancer, and their primary functions are to regulate the release of mature neutrophils from the bone marrow into the blood and to extend the survival of neutrophils (38,39). In addition, cytokines, including interleukins (IL-17A, IL-6) (10,12,25,40), interferons (IFN-b) (9), TNF-a (25), and TGF-b (5,8,24,28), have been linked to neutrophil recruitment and extended neutrophil survival, as well as regulating neutrophil function.…”

Section: Diffusible Mediators In the Tumor Nichementioning

confidence: 99%

The Recruitment of Neutrophils to the Tumor Microenvironment Is Regulated by Multiple Mediators

2021

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Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different mediators collaborate by integrating their signaling network, and particularly focus on TGF-β, a cytokine that is highly expressed in invasive tumors, and CXCR2 ligands, which are crucial neutrophil recruiting chemokines. Finally, we highlight gaps in the field and the need to expand current knowledge of the secretory machineries and cross-talks among mediators to develop novel neutrophil targeting strategies as effective therapeutic options in the treatment of cancer.

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“…One of the major signaling pathways triggered in neutrophils by a wide range of activating factors, including chemoattractants, is the extracellular signal–regulated kinase (ERK) pathway [63, 64]. ERK pathway is also important for activating the migration machinery of neutrophils [65].…”

Section: Resultsmentioning

confidence: 99%

“…Neutrophils have very short life spans, however recent studies point to the role of pro-inflammatory soluble mediators in extending neutrophil survival [64, 85]. Indeed, many of the soluble factors including CXCL8, G-CSF, and GM-CSF, secreted abundantly from the M4 and MDA-MB-231metastatic breast cancer cells, are known to have pro-survival effect on neutrophils [64, 85]. Hence, we envisage that the pro-survival effect of M4 secreted factors also underlie the persistence of more neutrophils near M4 spheroids.…”

Section: Discussionmentioning

confidence: 99%

TRIPLE-NEGATIVE BREAST CANCER CELLS RECRUIT NEUTROPHILS BY SECRETING TGF-β AND CXCR2 LIGANDS

SenGupta

Hein

et al. 2021

Preprint

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Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.

show abstract

Human neutrophils depend on extrinsic factors produced by monocytes for their survival response to TLR4 stimulation

Cited by 5 publications

References 48 publications

Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands

Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands

The Recruitment of Neutrophils to the Tumor Microenvironment Is Regulated by Multiple Mediators

TRIPLE-NEGATIVE BREAST CANCER CELLS RECRUIT NEUTROPHILS BY SECRETING TGF-β AND CXCR2 LIGANDS

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