Cited by 417Immune cells in cancerNeutrophil, Myeloperoxidase and Oxidative MechanismsCancer Immunotherapy and Biomarkers

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Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

Alfaro, Carlos, Teijeira, Alvaro, Oñate, Carmen, Pérez, Guiomar, Sanmamed, Miguel F., Andueza, Maria Pilar, Alignani, Diego, Labiano, Sara, Azpilikueta, Arantza, Rodriguez-Paulete, Alfonso, Garasa, Saray, Fusco, Juan P., Aznar, Angela, Inogés, Susana, De Pizzol, Maria, Allegretti, Marcello, Medina-Echeverz, Jose, Berraondo, Pedro, Perez-Gracia, Jose L., Melero, Ignacio·2016·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-15-2463

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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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Background
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Background
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BackgroundInfluential
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Background
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“Interestingly, tumors have been shown to produce IL-8, which attracts G-MDSCs to the tumor site and induce NET formation [52].”
Background
A Reconstructed Human Melanoma-in-Skin Model to Study Immune Modulatory and Angiogenic Mechanisms Facilitating Initial Melanoma Growth and Invasion
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Background
Increased intraocular inflammation in retinal vein occlusion is independent of circulating immune mediators and is involved in retinal oedema
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“For example, G-CSF and IL-8 can induce neutrophil extracellular traps (NETs), which can enhance coagulation (Demers et al., 2012; Alfaro et al., 2016; Thålin et al., 2019).”
Background
Cytokine Modification of Adoptive Chimeric Antigen Receptor Immunotherapy for Glioblastoma
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“For example, the chemokine IL-8 promotes the recruitment of tumor-associated neutrophils and MDSCs [92], angiogenesis [93], epithelial-mesenchymal transition [94], and cancer cell resistance, stemness, and metastatic potential [95].”
Background
NETosis - Dr. Jekyll and Mr. Hyde in inflammation
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Tumor cell density dependent IL-8 secretion induces the fluctuation of tregs/CD8 + T cells infiltration in hepatocellular carcinoma: one prompt for the existence of density checkpoint
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“Focusing on the recruitment of immunosuppressive cells alone can explain the immunosuppressive state related to IL-8, but the dual chemotactic effect of IL-8 also allows the recruitment of anti-tumor immune cells such as lymphocytes [39, 42, 43].”
Background
CXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis
Vermeersch, G., Proost, P., Struyf, S., Gouwy, M., & Devos, T. (2024) · Haematologica · doi:10.3324/haematol.2023.284921 · Cited by 16
A Therapeutic Whole-Tumor-Cell Vaccine Covalently Conjugated with a TLR7 Agonist
Chi, H., Hao, Y., Wang, X., Tang, L., Deng, Y., Chen, X., Gao, F., Sha, O., & Jin, G. (2022) · Cells · doi:10.3390/cells11131986 · Cited by 15
“dramatically when combined with the CXCR1/CXCR2 inhibitor reparixin, which is in clinical trials [26].”
Background
Cytotoxic necrotizing factor 1 hinders colon tumorigenesis induced by colibactin-producing Escherichia coli in Apc Min/+ mice
Chat, H., Dalmasso, G., Godfraind, C., Bonnin, V., Beyrouthy, R., Bonnet, M., Barnich, N., Mettouchi, A., Lemichez, E., Bonnet, R., et al. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2229569 · Cited by 16
Impact of obesity‑associated myeloid‑derived suppressor cells on cancer risk and progression (Review)
Jiménez‐Cortegana, C., Gutiérrez‐García, C., Sánchez-Jiménez, F., Vilariño‐García, T., Flores-Campos, R., Pérez‐Pérez, A., Garnacho, C., Sánchez‐León, M., García-Domínguez, D. J., Hontecillas‐Prieto, L., et al. (2024) · International Journal of Oncology · doi:10.3892/ijo.2024.5667 · Cited by 17
“Adipose tissue from obese patients with prostate cancer also mobilized IL‑8 [known as CXCL8 and an important chemoat‑ tractant for MDSCs (36)] to recruit adipose stromal cells into the TME and induce tumor growth and progression.”
Background
Molecular mechanism of gossypol mediating CCL2 and IL‑8 attenuation in triple‑negative breast cancer cells
Messeha, S. S., Zarmouh, N. O., Mendonca, P., Cotton, C., & Soliman, K. F. A. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11240 · Cited by 15
Multi-omics analysis reveals that neutrophil extracellular traps related gene TIMP1 promotes CRC progression and influences ferroptosis
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Circulating Levels of Monocytic Myeloid-Derived Suppressor Cells (M-MDSC) and CXCL-8 in Non-Small Cell Lung Cancer (NSCLC).
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Expressivity of Interleukin-8 and Gastric Cancer Prognosis Susceptibility: A Systematic Review and Meta-Analysis
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“IL-8 derived from tumours contributes to the chemotactic recruitment of granulocytes.(12) Meanwhile, IL-8 exerts direct pro-tumorigenic effects, including the promotion of angiogenesis, tumour cell dedifferentiation, invasion and/or metastasis.”
Background
Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses
Larkin, R. M., Lopez, D. C., Robbins, Y. L., Lassoued, W., Canubas, K., Warner, A., Karim, B. O., Vulikh, K., Hodge, J. W., Floudas, C. S., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05339-9 · Cited by 16
Prognostic impact of Interleukin-8 levels in lung cancer: A meta-analysis and a bioinformatic validation
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Nanoparticles for Directed Immunomodulation: Mannose-Functionalized Glycodendrimers Induce Interleukin-8 in Myeloid Cell Lines
Jatczak‐Pawlik, I., Gorzkiewicz, M., Studzian, M., Zinke, R., Appelhans, D., Klajnert‐Maculewicz, B., & Pułaski, Ł. (2021) · Biomacromolecules · doi:10.1021/acs.biomac.1c00476 · Cited by 14
Casting a NET on cancer: the multiple roles for neutrophil extracellular traps in cancer
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Association of Chemokines and Chemokine Receptor Expression with Monocytic-Myeloid-Derived Suppressor Cells during Tumor Progression
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“Additionally, some evidence suggests that chemokine receptors are differentially expressed by Mo-MDSCs and PMNMDSCs, which aids in their differential recruitment by C-C chemokine receptor type 2 (CCR2) and C-X-C chemokine receptor type 1 (CXCR1), type 2 (CXCR2), and type 4 (CXCR4) (17,19-24).”
Background
Immunotherapy-associated hemostatic abnormalities: bleeding and thrombotic complications
Li, Y., Jiang, H., Luo, L., & Mei, H. (2025) · Annals of Hematology · doi:10.1007/s00277-025-06482-z · Cited by 14
“(2) Elevated levels of MDSCs and proinflammatory factors such as IL-8 in peripheral blood prior to treatment induce platelet activation and the release of neutrophil extracellular traps, increasing the risk of ICI-associated VTE [10, 65].”
Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy
Zhang, Z., Cui, D., Wang, H., Wu, L., & Liu, X. (2026) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-025-04278-8 · Cited by 13
“To counteract this, CAR-T cells have been engineered to express chemokine receptors matching the tumor’s chemokine profile [127–129].”
Monocytic-Myeloid Derived Suppressor Cells Suppress T-Cell Responses in Recovered SARS CoV2-Infected Individuals
Beliakova‐Bethell, N., Maruthai, K., Xu, R., Salvador, L. C. M., & Garg, A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.894543 · Cited by 14
“Although the mechanism of IL-8 (CXCL8) mediated MMDSC expansion is not established, IL-8 facilitates differentiation and subsequent mobilization of MDSC in patients diagnosed with several types of cancers (91, 92).”
Background
Combining all-trans retinoid acid treatment targeting myeloid-derived suppressive cells with cryo-thermal therapy enhances antitumor immunity in breast cancer
Lou, Y., Peng, P., Wang, S., Wang, J., Du, P., Zhang, Z., Zheng, J., Liu, P., & Xu, L. X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1016776 · Cited by 14
Interferon-α induces differentiation of cancer stem cells and immunosuppression in hepatocellular carcinoma by upregulating CXCL8 secretion
Ma, Y.-T., Zheng, L., Zhao, C.-W., Zhang, Y., Xu, X., Wang, X., Niu, G., Man, Z.-S., Gu, F., & Chen, Y. (2024) · Cytokine · doi:10.1016/j.cyto.2024.156555 · Cited by 13
Neonatal low-density granulocytes internalize and kill bacteria but suppress monocyte function using extracellular DNA
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Neutrophil Extracellular Traps in Digestive Cancers: Warrior or Accomplice
Chen, Y., Han, L., Qiu, X., Wang, G., & Zheng, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.766636 · Cited by 12
“Glioblastoma (50) CXCR2 – IL-8 derived from patients’ plasma and culture medium of HT29 cell could provoke neutrophils to extrude NETs.”
BackgroundInfluential
Blood Biomarkers of Response to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer
Lage, Y., Olmedo, M. E., Rueda, A. G., Ballesteros, P. Á., Rodríguez, D. R., & Velasco, M. T. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11113245 · Cited by 15
Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients
Baci, D., Cekani, E., Imperatori, A. S., Ribatti, D., & Mortara, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.914890 · Cited by 12
“N2 TANS enhances the immunosuppressive milieu by expressing high levels of PD-L1, arginase-1 (ARG1), reactive oxygen species (ROS), nitric oxide (NO), IL-10, and TGFb1, shaping the tumor landscape and impairing T-cell-mediated cytotoxicity (42) The expression of both CXCL8 and Arg-1 by neutrophils is correlated with I…”
BackgroundInfluential
Genetic polymorphisms in interleukin-1β (rs1143634) and interleukin-8 (rs4073) are associated with survival after resection of intrahepatic cholangiocarcinoma
Lurje, I., Gaisa, N. T., Dahl, E., Knüchel, R., Strnad, P., Trautwein, C., Tacke, F., Neumann, U. P., Czigány, Z., & Lurje, G. (2023) · Scientific Reports · doi:10.1038/s41598-023-39487-7 · Cited by 12
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“The chemotactic effects of the IL-8/IL-18 signaling pathway on MDSCs, neutrophils, and other myeloid cells [75,76] may contribute to the acquired resistance against ICIs.”
Background
Myeloid-derived suppressor cells attenuate the antitumor efficacy of radiopharmaceutical therapy using 90Y-NM600 in combination with androgen deprivation therapy in murine prostate tumors
Muralidhar, A., Hernandez, R. T., Morris, Z. S., Rojas, H. C., Idrissou, M. B., Weichert, J. P., & McNeel, D. G. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008760 · Cited by 13
Low‐Density Neutrophils: Enigmatic Cells in Health and Disease
Blanco-Camarillo, C., & Rosales, C. (2025) · Journal of Immunology Research · doi:10.1155/jimr/3037744 · Cited by 13
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Stenzel, A. E., Abrams, S. I., & Moysich, K. B. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01608 · Cited by 11
“IL-8 can be produced by cancer cells within the tumor, demonstrating the cancer’s ability to evade apoptosis through increasing these immunosuppressive MDSCs (14, 16).”
Background
Immunosuppressive effects and mechanisms of three myeloid-derived suppressor cells subsets including monocytic-myeloid-derived suppressor cells, granulocytic-myeloid-derived suppressor cells, and immature-myeloid-derived suppressor cells
Nagatani, Y., Funakoshi, Y., Suto, H., Imamura, Y., Toyoda, M., Kiyota, N., Yamashita, K., & Minami, H. (2021) · Journal of Cancer Research and Therapeutics · doi:10.4103/jcrt.jcrt_1222_20 · Cited by 11
Suggested role for neutrophil extracellular trap formation in Ewing sarcoma immune microenvironment
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Residual immune activation in HIV-Infected individuals expands monocytic-myeloid derived suppressor cells
Singh, R., Chakraborty, M., Gautam, A., Roy, S. K., Halder, I., Barber, J., & Garg, A. (2021) · Cellular Immunology · doi:10.1016/j.cellimm.2021.104304 · Cited by 10
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Background
Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles
Wang, Y., Lin, A., Liu, Z., Cheng, Q., Zhang, J., & Luo, P. (2026) · 癌症：英文版 · doi:10.34133/cancomm.0008 · Cited by 10
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Background
The role of extracellular vesicles and interleukin-8 in regulating and mediating neutrophil-dependent cancer drug resistance
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BackgroundSelf-citation
A Narrative Review: Immunometabolic Interactions of Host–Gut Microbiota and Botanical Active Ingredients in Gastrointestinal Cancers
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Background
Dual Nature of Neutrophil Extracellular Traps (NETs)—From Cancer’s Ally to Therapeutic Target
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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: Alfaro, Carlos
Oñate, Carmen
Sanmamed, Miguel F.
Andueza, Maria Pilar
Alignani, Diego
Labiano, Sara
Azpilikueta, Arantza
Garasa, Saray
Inogés, Susana
Allegretti, Marcello
Berraondo, Pedro
Melero, Ignacio
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2016-07-31
Volume: 22
Issue: 15
Pages: 3924-3936
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-15-2463
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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Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

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