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Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)
Published version of a preprint
Abstract
Purpose: Myeloid-derived suppressor cells (MDSC) are considered an important T-cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes. Experimental Design: MDSC were characterized and sorted by multicolor flow cytometry on ficoll-gradient isolated blood leucokytes from healthy volunteers (n = 10) and advanced cancer patients (n = 28). In chemotaxis assays, sorted granulocytic and monocytic MDSC were tested in response to recombinant IL8, IL8 derived from cancer cell lines, and patient sera. Neutrophil extracellular traps (NETs) formation was assessed by confocal microscopy, fluorimetry, and time-lapse fluorescence confocal microscopy on short-term MDSC cultures. Results: IL8 chemoattracts both granulocytic (GrMDSC) and monocytic (MoMDSC) human MDSC. Monocytic but not granulocytic MDSC exerted a suppressor activity on the proliferation of autologous T cells isolated from the circulation of cancer patients. IL8 did not modify the T-cell suppressor activity of human MDSC. However, IL8 induced the formation of NETs in the GrMDSC subset. Conclusions: IL8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control. Clin Cancer Res; 22(15); 3924–36. ©2016 AACR.
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“These cytokines could enhance migration of macrophages and MDSCs to the liver [64, 65] (Fig. 2).”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [65]
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CXCL8 in Tumor Biology and Its Implications for Clinical Translation
Xiong, X., Liao, X., Qiu, S., Xu, H., Zhang, S., Wang, S., Ai, J., & Yang, L. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.723846 · Cited by 129
“Interestingly, CXCL8 can recruit the both subtypes of MDSCs to TME, but they play different functions (Alfaro et al., 2016).”
BackgroundIncreased incidence of venous thromboembolism with cancer immunotherapy
Roopkumar, J., Swaidani, S., Kim, A. S., Thapa, B., Gervaso, L., Hobbs, B. P., Wei, W., Alban, T. J., Funchain, P., Kundu, S., et al. (2021) · Med · doi:10.1016/j.medj.2021.02.002 · Cited by 130
González-Aparicio, M., & Alfaro, C. (2019) · Journal of Immunology Research · doi:10.1155/2019/6252138 · Cited by 123
“We have verified in previous works [57] that IL-8 is a chemokine produced by cancer cells and whose serum concentration correlates with the tumor burden of patients and with a poor prognosis of the disease.”
BackgroundInfluentialSelf-citationShang, A., Gu, C., Zhou, C., Yang, Y., Chen, C., Zeng, B., Wu, J., Lu, W., Wang, W., Sun, Z., et al. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-0517-1 · Cited by 126
Tuning the Tumor Myeloid Microenvironment to Fight Cancer
Jahchan, N. S., Mujal, A. M., Pollack, J. L., Binnewies, M., Sriram, V., Reyno, L. M., & Krummel, M. F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01611 · Cited by 124
“Emerging data suggest that tumor-produced IL-8 (CXCL8) plays an important role in recruiting neutrophils and monocytes into the TME of many cancer types (131).”
BackgroundPlatelets in the NETworks interweaving inflammation and thrombosis
Wienkamp, A.-K., Erpenbeck, L., & Rossaint, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.953129 · Cited by 125
Huang, M., Wu, R., Chen, L., Peng, Q., Li, S., Zhang, Y., Zhou, L., & Duan, L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02243 · Cited by 113
“CXC-motif chemokines such as CXCL12 and IL-8 are also involved in the recruitment of MDSCs (41, 42).”
Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance
Furumaya, C., Martínez-Sanz, P., Bouti, P., Kuijpers, T. W., & Matlung, H. L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02100 · Cited by 114
“The neutrophil chemoattractant IL-8, which is produced in the TME, has been suggested to induce NET formation (39).”
BackgroundInfluentialSacchi, A., Grassi, G., Bordoni, V., Lorenzini, P., Cimini, E., Casetti, R., Tartaglia, E., Marchioni, L., Petrosillo, N., Palmieri, F., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03125-1 · Cited by 115
Gut microbiota-mediated immunomodulation in tumor
Liu, X., Chen, Y., Zhang, S., & Dong, L. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01983-x · Cited by 112
Neutrophil Extracellular Traps, Angiogenesis and Cancer
Poto, R., Cristinziano, L., Modestino, L., de Paulis, A., Marone, G., Loffredo, S., Galdiero, M. R., & Varricchi, G. (2022) · Biomedicines · doi:10.3390/biomedicines10020431 · Cited by 120
In vivo evidence for extracellular DNA trap formation
Yousefi, S., Simon, D., Stojkov, D., Васильевна, К. А., Karaulov, A. V., & Simon, H. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2497-x · Cited by 115
Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis
Khan, U., Chowdhury, S., Billah, M. M., Islam, K. M. D., Thorlacius, H., & Rahman, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147260 · Cited by 112
“IL-8 acts as a multifaceted chemotactic stimulus utilized by neoplastic cells to foster transmigration and angiogenesis concurrently [92,93].”
BackgroundPalangat, M., Anastasakis, D. G., Fei, D. L., Lindblad, K. E., Bradley, R. K., Hourigan, C. S., Hafner, M., & Larson, D. R. (2019) · Genes & Development · doi:10.1101/gad.319590.118 · Cited by 101
“Since IL8 also contributes to recruitment of myeloid cells that suppress an adaptive immune response (Alfaro et al. 2016; Dominguez et al. 2017), one prediction is that cells with U2AF1 mutations or perhaps splicing factor mutations in general will be refractory to immuno-therapy unless treated…”
The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.09.001 · Cited by 101
de Andrea, C. E., Ochoa, M. C., Villalba-Esparza, M., Teijeira, Á., Schalper, K. A., Abengozar‐Muela, M., Eguren‐Santamaría, I., Sainz, C., Sánchez‐Gregorio, S., Garasa, S., et al. (2021) · The Journal of Pathology · doi:10.1002/path.5753 · Cited by 103
“As positive controls and standards, we used NETs induced in isolated neutrophils from healthy donors and cancer patients with PMA or IL-8 [40], rendering linear ranges of quantitative detection based on simultaneous NETs in solid tumours 195”
MethodSelf-citationConvergent inducers and effectors of T cell paralysis in the tumour microenvironment
Hanahan, D., Michielin, O. A., & Pittet, M. J. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00761-z · Cited by 106
“178–181), which can be secreted by cancer cells and other cell types within the TME.”
Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond
Zhao, Y., Du, J., & Shen, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1157537 · Cited by 107
Formation of Neutrophil Extracellular Traps under Low Oxygen Level
Branitzki‐Heinemann, K., Möllerherm, H., Völlger, L., Husein, D. M., de Buhr, N., Blodkamp, S., Reuner, F., Brogden, G., Naim, H. Y., & von Köckritz‐Blickwede, M. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00518 · Cited by 106
“(54) demonstrated that tumor-produced IL-8 leads to extrusion of NETs in human myeloid-derived suppressor cells, which are considered an important T-cell immunosuppressive component in cancer-bearing hosts (54).”
BackgroundGuan, X., Lu, Y., Zhu, H., Yu, S., Zhao, W., Chi, X., Xie, C., & Yin, Z. (2021) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s303588 · Cited by 100
Zalfa, C., & Paust, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.633205 · Cited by 100
Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy
Hao, Z., Li, R., Wang, Y., Li, S., Hong, Z., & Han, Z. (2021) · Biomarker Research · doi:10.1186/s40364-021-00333-5 · Cited by 101
“observed in MDSC motivation, including CCL2/CCR 2[19], CCL15/CCR 1[20], CCL9/CCR 1[21], CXCL1/ CXCL2/CXCL3 with receptor CXCR 2[22–25], CXCL12/CXCR 4[26, 27], and CXCL8 (IL-8) with receptor CXCR1/CXCR 2[28].”
Fang, Q., Stehr, A. M., Naschberger, E., Knopf, J., i, M. H., & Stürzl, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1075260 · Cited by 102
“Blocking of CXCR1 and CXCR2 with Reparixin or a CXCR1 blocking monoclonal antibody (mAb) inhibited NET formation induced by the respective CM (61, 74).”
BackgroundInfiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase
Lerman, I., García-Hernández, M. D. L. L., Rangel‐Moreno, J., Chiriboga, L. A., Pan, C., Nastiuk, K. L., Krolewski, J. J., Sen, A., & Hammes, S. R. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0003 · Cited by 91
“Indeed, prostate cancer patients have elevated plasma concentrations of G-CSF and IL8, two factors that likely prime circulating and infiltrating granulocyticMDSCs forNETosis (24, 27).”
BackgroundBendib, I., de Chaisemartin, L., Granger, V., Schlemmer, F., Maître, B., Hüe, S., Surénaud, M., Beldi‐Ferchiou, A., Carteaux, G., Razazi, K., et al. (2019) · Anesthesiology · doi:10.1097/aln.0000000000002619 · Cited by 91
Cristinziano, L., Modestino, L., Loffredo, S., Varricchi, G., Braile, M., Ferrara, A. L., de Paulis, A., Antonelli, A., Marone, G., & Galdiero, M. R. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900543 · Cited by 88
“Both CXCL8/IL-8 and GM-CSF were able to induce NET release from neutrophils and play central roles in the maintenance of the TME (18, 46, 47).”
BackgroundInfluentialThe Resistance Mechanisms of Lung Cancer Immunotherapy
Wang, F., Wang, S., & Zhou, Q. H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.568059 · Cited by 90
“It potently regulates the chemotaxis of neutrophils (221, 222) and exerts direct pro-tumorigenic effects (223).”
BackgroundLiu, S., Wu, W., Du, Y., Yin, H., Chen, Q., Yu, W., Wang, W., Yu, J., Liu, L., Lou, W., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01843-6 · Cited by 93
“These ligands are known to be abundantly secreted in most cancers and play a pivotal role in regulating the recruitment and functions of TANs [58, 59].”
BackgroundMyeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence
Salminen, A., Kauppinen, A., & Kaarniranta, K. (2018) · Biogerontology · doi:10.1007/s10522-018-9762-8 · Cited by 84
Cedervall, J., Dragomir, A., Saupe, F., Zhang, Y., Ärnlöv, J., Larsson, E., Dimberg, A., Larsson, A. O., & Olsson, A. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1320009 · Cited by 89
“Additional tumorderived factors such as IL-8, a potent chemotactic factor for myeloid cells, has also been implicated in cancer-associated NETosis.18 Recent reports have provided further evidence for a role of NETs in cancer-associated pathology in humans.19 Two studies show a correlation between NETs and a hypercoagu…”
BackgroundInfluential
Metadata
- Authors
- Alfaro, C., Teijeira, A., Oñate, C., Pérez, G., Sanmamed, M. F., Andueza, M. P., Alignani, D., Labiano, S., Azpilikueta, A., Rodriguez-Paulete, A., Garasa, S., Fusco, J. P., Aznar, A., Inogés, S., De Pizzol, M., Allegretti, M., Medina-Echeverz, J., Berraondo, P., Perez-Gracia, J. L., & Melero, I.
- Affiliations
- Clinica Universidad de Navarra (ES)
- 1Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain.
- Centro de Investigación Médica Aplicada (ES)
- 5Dompé Farmaceutici SpA, L'Aquila, Italy.
- 2Department of Oncology, University Clinic of Navarra, Pamplona, Spain.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-07-31
- Volume
- 22
- Issue
- 15
- Pages
- 3924-3936
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2298626553
- Cited by
- 417
- References
- 53
- Citations by year
- 2026: 35 · 2025: 33 · 2024: 44 · 2023: 54 · 2022: 54 · 2021: 59 · 2020: 46 · 2019: 35 · 2018: 22 · 2017: 21 · 2016: 13
- FWCI
- 18.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- interleukin-8, myeloid-derived suppressor cells, neutrophil extracellular traps, tumor microenvironment, chemotaxis, granulocytic MDSCs, monocytic MDSCs, T cell suppression, tumor immunosuppression, tumor-derived cytokines
- MeSH terms
- Myeloid-Derived Suppressor Cells, Animals, Chemotaxis, Leukocyte, Disease Models, Animal, Humans, Neoplasms, Neutrophils, Sulfonamides, Biomarkers, T-Lymphocyte Subsets, Interleukin-8, Mice, Knockout, Cell Line, Tumor, Mice, Extracellular Traps
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