The DOI matches its Crossref record; 52 of the 53 references it cites were found in a registry or an index.
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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Gillot, C., Favresse, J., Mullier, F., Lecompte, T., Dogné, J., & Douxfils, J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.708302 · Cited by 57
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“Consistently, activation of XBP-1 in a xenograft model of human glioma leads to the induction of proangiogenic inflammatory factors such as IL-6, -8, and -1 (6), known to promote neutrophil and MDSC infiltration into the TME, resulting in CC immunotolerance (3, 15).”
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Thrombotic Complications Associated with Immune Checkpoint Inhibitors
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BackgroundTargeting neutrophils for cancer therapy
Kwak, J., & Houghton, A. M. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01210-8 · Cited by 54
“Experimen-tally, many of the reagents capable of inducing NET formation, such as phorbol myristate acetate, CXCL1, CXCL2, CXCL5, IL-8, granulocyte colony-stimulating factor (G-CSF), and lipopolysaccharides, are well known to activate neutrophils 124–126 .”
Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy
Takacs, G. P., Flores‐Toro, J., & Harrison, J. K. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107790 · Cited by 47
“Abbreviations: ARG1 Arginase 1 BBB Blood-brain barrier C Cysteine CAR-T Chimeric antigen receptor T-cell CCL2/MCP1 Chemokine ligand 2 CCL7/MCP3 Chemokine ligand 7 CCR2 Chemokine receptor 2 CNS Central nervous system CTL Cytotoxic lymphocytes CTLA-4 Cytotoxic T-lymphocyte-associated protein-4 CXCL8 Interleukin-8 DC Den…”
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“CXCL2 has been shown to not only mediate neutrophil che-motaxis, but is also sufficient to stimulate NET formation (Alfaro et al., 2016; Nie et al., 2019; Teijeira et al., 2020).”
Krawczyk, K. M., Nilsson, H., Allaoui, R., Lindgren, D., Arvidsson, M., Leandersson, K., & Johansson, M. (2017) · Laboratory Investigation · doi:10.1038/labinvest.2017.78 · Cited by 43
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Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled
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“In addition, by acting in a paracrine manner, IL-8/IL-8R axis has a prominent role in promoting a favorable tumor microenvironment by recruiting immune cells characterized by permissive phenotype for tumor growth, such as N2-neutrophils Frontiers in Oncology 03 and myeloid-derived suppressor cells (MDSCs) (32).”
BackgroundInfluentialAdvances in promoting chimeric antigen receptor T cell trafficking and infiltration of solid tumors
Hong, M., Talluri, S., & Chen, Y. Y. (2023) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2023.103020 · Cited by 42
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“Critically, IL-8 has been shown to have pro-tumoural effects; so, strategies that utilise IL-8, such as ectopic CXCR1/2 expression, must acknowledge the possible tumour potentiating effects [57].”
BackgroundTRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma
Favaro, F., Luciano‐Mateo, F., Moreno‐Càceres, J., Hernández-Madrigal, M., Both, D., Montironi, C., Püschel, F., Nadal, E., Eldering, E., & Muñoz‐Pinedo, C. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05495-0 · Cited by 41
“The best characterized inflammatory roles of IL-8 in lung cancer are neutrophil and myeloidderived suppressor cell (MDSC) attraction [7, 8], as well as Neutrophil Extracellular Trap (NET) formation [7, 9], which might be involved in metastatic spread [10].”
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“IL6 and IL8 are inflammatory cytokines, which are often associated with worse disease prognosis (69, 70), immunosuppressive myeloid-derived suppressor cells (71, 72), and reduced efficacy of ICI therapies (73–77).”
BackgroundPeriodontal sources of citrullinated antigens and TLR agonists related to RA
Vitkov, L., Hannig, M., Minnich, B., & i, M. H. (2018) · Autoimmunity · doi:10.1080/08916934.2018.1527907 · Cited by 40
“[27,43,44], and neutrophil-produced ROS [45].”
Zhang, Z., Zhu, Q., Wang, S., & Shi, C. (2022) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-022-04550-w · Cited by 39
“Interleukin 8, also known as CXCL8, is an effective chemokine for neutrophils [11, 12].”
BackgroundPatterns and functional implications of platelets upon tumor “education”
Zhang, Q., Liu, H., Zhu, Q., Zhan, P., Zhu, S., Zhang, J., Lv, T., & Song, Y. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.07.018 · Cited by 39
“Briefly, tumor derived granulocyte colony-stimulation factor (G-CSF) can induce neutrophils to release NETs, which causes platelet activation and aggregation (Alfaro et al. , 2016, Cedervall et al. , 2016).”
Li, P., Chen, X., Qin, G., Yue, D., Zhang, Z., Yü, P., Wang, D., Zhao, X., Song, M., Zhao, Q., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0415 · Cited by 40
“IL8, regulated by MAEL, positively correlated with patient prognosis Accumulating evidence suggests that TME plays a crucial role in promoting the development of solid cancers (11, 26).”
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Addressing the obstacles of CAR T cell migration in solid tumors: wishing a heavy traffic
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“Certain tumor cells express particular chemokines that have various benefits for them including the promotion of invasiveness and the formation of tumor-associated blood vessels, as well as acting as mediators of metastasis and attractors of specific immune suppressor cells [95,96].”
BackgroundThe Interplay Between Inflammation and Stromal Components in Pancreatic Cancer
Li, Y., Wang, J., Wang, H., Zhang, S., Wei, Y., & Liu, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.850093 · Cited by 40
“The CXCR1/2 blocking agent reparixin abolishes or reverses the above effects to a certain extent (31).”
BackgroundComprehensive analysis of the expression and prognostic value of CXC chemokines in colorectal cancer
Li, Y., Yang, X., Xu, C., Sun, J., Fang, Z., Pan, H., & Han, W. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107077 · Cited by 38
Yue, D., Liu, S., Zhang, T., Wang, Y., Qin, G., Chen, X., Zhang, H., Wang, D., Huang, L., Wang, F., et al. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0290 · Cited by 38
“The immunosuppressive effects of MDSCs are relatively well-studied in patients with cancer 7-9 .”
The Formation of NETs and Their Mechanism of Promoting Tumor Metastasis
Li, J., Chen, J., Sun, J., & Li, K. (2023) · Journal of Oncology · doi:10.1155/2023/7022337 · Cited by 39
“Signaling of IL-8 to CXCR2 initiates the PI3K/AKT/reactive oxygen species (ROS) signaling cascade essential for NETs production.”
BackgroundInfluentialJafarzadeh, A., Nemati, M., & Jafarzadeh, S. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116688 · Cited by 38
The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior
Wang, H., Zhang, Y., Wang, Q., Wei, X., Wang, H., & Gu, K. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00708-z · Cited by 40
Piro, G., Carbone, C., Agostini, A., Esposito, A., Pizzol, M. D., Novelli, R., Allegretti, M., Aramini, A., Caggiano, A., Granitto, A., et al. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-02028-6 · Cited by 37
“in our cancer models and [45] highlights the remarkable potential impact of IL-8 inhibition for cancer treatment.”
BackgroundSelf-citationRosell, A., Aguilera, K., Hisada, Y., Schmedes, C. M., Mackman, N., Wallén, H., Lundström, S., & Thålin, C. (2021) · Scientific Reports · doi:10.1038/s41598-021-84476-3 · Cited by 37
Mechanisms of Neutrophil Extracellular Trap Formation and Regulation in Cancers
Zhang, Z., Niu, R., Zhao, L., Wang, Y., & Liu, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210265 · Cited by 36
“On the one hand, myeloid-derived suppressor cells (MDSCs) can produce NETs under the stimulation of IL-8 [16], and at the same time, in the tumor which can release neutrophils extracellular traps (NETs) to capture and kill extracellular microor- ganisms.”
BackgroundInfluentialGao, M., Wu, X., Jiao, X., Hu, Y., Wang, Y., Zhuo, N., Dong, F., Wang, Y., Wang, F., Cao, Y., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006616 · Cited by 35
Missing in action—The meaning of cell death in tissue damage and inflammation
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Gibellini, L., Borella, R., Santacroce, E., Serattini, E., Boraldi, F., Quaglino, D., Aramini, B., Biasi, S. D., & Cossarizza, A. (2023) · Cancers · doi:10.3390/cancers15133327 · Cited by 35
“Interestingly, CXCL8 also induces granulocytic MDSCs to release NETs [80].”
BackgroundTraps N' Clots: NET-Mediated Thrombosis and Related Diseases
Stakos, D., Skendros, P., Konstantinides, S., & Ritis, K. (2020) · Thrombosis and Haemostasis · doi:10.1055/s-0039-3402731 · Cited by 36
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Neutrophils in glioma microenvironment: from immune function to immunotherapy
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Interferon Signaling in Estrogen Receptor–positive Breast Cancer: A Revitalized Topic
Fu, X., Angelis, C. D., & Schiff, R. (2021) · Endocrinology · doi:10.1210/endocr/bqab235 · Cited by 33
Prajapati, D. R., Molczyk, C., Purohit, A., Saxena, S., Sturgeon, R., Davé, B. J., Sushil Kumar, K., Batra, S. K., & Singh, R. K. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216185 · Cited by 34
In vitro study: HIF-1α-dependent glycolysis enhances NETosis in hypoxic conditions
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Interleukin-8 in the Tumor Immune Niche: Lessons from Comparative Oncology
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Janus-Faced Neutrophil Extracellular Traps in Periodontitis
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“Further, NET formation is directly induced by many oral bacteria from the dental plaque (41, 47, 68, 69), neutrophil pro-inflammatory chemokines (9, 13, 70), and neutrophil-produced ROS (24).”
BackgroundMitchell, K. G., Amini, B., Wang, Y., Carter, B. W., Godoy, M. C. B., Parra, E. R., Behrens, C., Villalobos, P. A., Reuben, A., Lee, J. J., et al. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02560-5 · Cited by 32
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Targeting Neutrophil Extracellular Traps: A Novel Antitumor Strategy
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“Ultimately, IL-8-induced NETs can entrap cancer cells and suppress T cells, thus shaping a protumoral environment [45].”
BackgroundArebro, J., Towle, R. M., Lee, C.-M., Bennewith, K. L., & Garnis, C. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1240159 · Cited by 30
Hsu, P.-C., Chen, Y., Cheng, C., Kuo, C., & Sytwu, H. (2021) · Life · doi:10.3390/life11050423 · Cited by 30
“Both IL-6 and IL-8 can induce chemotactic activities and direct neutrophils and monocytes to inflammatory tissues [17,18], and both the IL-6/STAT3 and IL-8/STAT3 axes mediate malignancies, cancer stemness, and immune suppression [14,19].”
BackgroundSeman, B. G., & Robinson, C. M. (2021) · Pathogens · doi:10.3390/pathogens10091091 · Cited by 28
Neutrophils: Musketeers against immunotherapy
Zahid, K. R., Raza, U., Tumbath, S., Jiang, L., Xu, W., & Huang, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.975981 · Cited by 31
“In triple-negative breast tumor patients, the phase I clinical trial (NCT02001974) to evaluate the safety of the oral administration of CXCR1/2 inhibitor reparixin has been conducted combined with paclitaxel (261).”
BackgroundInfluentialCao, J. W., Lake, J. A., Impastato, R. A., Chow, L., Perez, L., Chubb, L. S., Kurihara, J. N., Verneris, M. R., & DOW, S. W. (2024) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-024-03642-4 · Cited by 30
“CXCR2 is of particular interest because its primary ligand CXCL8 exerts strong pro-tumor effects through recruitment of myeloid derived suppressor cells (MDSCs) [45], enhancement of angiogenesis [46] and increased tumor metastases [44, 47].”
BackgroundEffect of microwave ablation treatment of hepatic malignancies on serum cytokine levels
Zhao, J., Li, Q., Muktiali, M., Ren, B., Hu, Y., Li, D., Li, Z., Li, D., Xie, Y., Tao, M., et al. (2020) · BMC Cancer · doi:10.1186/s12885-020-07326-x · Cited by 28
“However, recent studies have indicated that IL-8, both macrophageand cancer cell-derived, can recruit Myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment, eventually inhibiting antitumor immunity and promoting cancer progression [14, 15].”
Masuhiro, K., Tamiya, M., Fujimoto, K., Koyama, S., Naito, Y., Osa, A., Hirai, T., Suzuki, H., Okamoto, N., Shiroyama, T., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.157915 · Cited by 30
Radiation dose, schedule, and novel systemic targets for radio-immunotherapy combinations
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Role of myeloid-derived suppressor cells in the formation of pre-metastatic niche
Ya, G., Ren, W., Qin, R., He, J., & Zhao, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.975261 · Cited by 28
Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases
Korpics, M., Onderdonk, B., Dadey, R., Hara, J., Karapetyan, L., Zha, Y., Karrison, T., Olson, A., Fleming, G., Weichselbaum, R., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162260 · Cited by 26
“…protumor and immunosuppressive functions of IL-8 have been described via several mechanisms, including, but not limited to, myeloid-derived suppressor cells and neutrophil extracellular traps, angiogenesis and metastasis, epithelial-mesenchymal transition, and renewal of cancer stem cells (50–55).”
Bazargan, S., Bunch, B. L., Ojwang’, A. M. E., Blauvelt, J. L., Landin, A., Ali, J. R., Abrahams, D. F., Cox, C. A., Hall, A. M., Beatty, M. S., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1275375 · Cited by 30
“Mice do not have the IL-8 gene, and therefore we cannot make comparisons with the human data (38).”
Result
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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