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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Identification and single-cell analysis of prognostic genes related to mitochondrial and neutrophil extracellular traps in bladder cancer
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Advances in the mechanism and therapeutic potential of neutrophil extracellular traps in cancer promotion
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Targeting the IL-8 axis in high-risk myelodysplastic syndromes: a clinical experience with antibody blockade combined with decitabine/cedazuridine
Mina, A. A., Calvo, K. R., McKinnon, K. M., Raman, A. T., Wang, W., Cunningham, L., Liu, Y., Alexander, R., Larson, D. R., Pavletic, S. Z., et al. (2026) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2026.2661078 · Cited by 1
“Interleukin-8 (IL-8, CXCL8 ) is a proinflammatory chemokine and potent chemoattractant of granulocytes, myeloid derived suppressor cells (MDSC), and other inflammatory modulators [4,5].”
Distinct protein and metabolic profiles in patients with advanced clear-cell renal cell carcinoma treated with sunitinib: a study of the Spanish oncology genitourinary group
Quintás‐Cardama, A., Sanmartín, E., Garcia-Gimenez, A., Muñoz-Langa, J., Collado, A., Suárez, C., del Muro, X. G., Méndez-Vidal, M. J., García-Sánchez, J., Coloma, C. S., et al. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1639330 · Cited by 1
“Moreover, high levels of citrulline have been associated with immunosuppression by enhancing the proliferation of MDSCs in cancer patients.”
Influential
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“In addition, tumor cells have been found to secrete IL-8, attract myeloid-derived suppressor cells, and activate neutrophil precursors to release NETs (72).”
IL-8 blockade enhances anti-PD-1 therapeutic activity in renal cell carcinoma in a next-generation patient-derived xenograft model
Sobu, R., Kobayashi, Y., Kashima, S., Inoue, T., Sumiyoshi, T., Hamana, H., Takeda, M., Hiroshima, Y., Seki, S., Fujiyama, N., et al. (2026) · iScience · doi:10.1016/j.isci.2026.116386 · Cited by 1
“In comparison to these T-cell-related findings with modest effect sizes, the frequency of M-MDSCs in peripheral blood cells remained consistently higher in NR at all time points.”
Influential
An InDel genomic variant within a bifunctional super-enhancer for LINC00636 and CD47 regulation in breast cancer
Benedetto, C. D., Tsark, A., Acenas, D. D., Thach, A., Singhal, A., Opazo-Mellado, V., Rodriguez-Lemus, A., Zeini, M. E., Zhang, H., Park, C., et al. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06456-y · Cited by 1
Targeting tumor microenvironment-associated cells to reverse therapy resistance
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A Positive Feedback DNA-PK/MYT1L-CXCR1-ERK1/2 Proliferative Signaling Loop in Glioblastoma
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“The tumor-produced IL-8 is a potent chemoattractant that recruits CXCR1/2-expressing human myeloid-derived suppressor cells to tumor foci, playing a crucial role in immune resistance [63].”
Progress in the mechanistic understanding of NETs formation in cancer
Luo, C., Xie, X., Fang, C., Yu, B., Qian, X., Hong, W., Hong, S., Li, H., Wang, Y., & Li, Y. (2025) · Medical Oncology · doi:10.1007/s12032-025-03010-x · Cited by 1
“In 2016, Carlos et al. reported that IL-8 promotes neutrophil DNA extrusion in human colorectal cancer models, facilitating cancer cell proliferation and metastasis [45].”
Associations between NETosis-related genes and 28-day mortality in patients with sepsis: An observational retrospective study and bioinformatic analysis
Liu, Y., & Chen, L. (2025) · Science Progress · doi:10.1177/00368504251374929 · Cited by 1
“24 C-X-C motif chemokine receptor 2 (CXCR2), a chemokine receptor predominantly expressed on leukocytes, plays a pivotal role in the pathogenesis of various in ﬂ ammatory conditions.”
Immune Gene Therapy of Cancer
Esmaeilzadeh, A., Jafari, D., Ghaebi, M., Elahi, R., Afshari, F., & Karimi, L. (2025) · Springer eBooks · doi:10.1007/978-3-032-00767-4_202 · Cited by 1
Cancer Immunotherapy
DOW, S. W., & Guth, A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-323-59496-7.00014-1 · Cited by 1
"Correlation between Serum Interleukin-8, Interleukin-6 Levels, and the Response to Anti-PD-1/PD-L1 Inhibitor in Patients with Malignant Tumors: A Prospective Observational Study"
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H.Pylori Infection Induces CXCL8 Expression and Promotes Gastric Cancer Progress Through Downregulating KLF4Preprint
Liu, Z., Wu, X. N., Tian, Y., zhang, W., qiao, S., Xu, W., liu, Y., & Wang, S. (2020) · doi:10.21203/rs.3.rs-21028/v1 · Cited by 1
Neutrophils recruited by NKX2-1 suppression via activation of CXCLs/CXCR2 axis promote lung adenocarcinoma progressionPreprint
La’ah, A. S., Tsai, P., Yarmishyn, A. A., Ching, L., Chien, Y., Chen, J. C., Tsai, M., Chen, Y., Ma, C., Hsu, P., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3646385/v1 · Cited by 1
Identification of functional single nucleotide polymorphisms (SNPs) in High Risk-Human Papillomavirus (HR-HPV) related diseases
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Владимировна, К. Е., Sholokhov, L. F., & Belokrinitskaya, T. E. (2019) · International Conference on Health and Wellbeing in Modern Society (ICHW) · doi:10.2991/ichw-19.2019.33
Neonatal granulocytic MDSCs possess phagocytic properties during bacterial infectionPreprint
Seman, B. G., Vance, J. K., Witt, M. R., & Robinson, C. M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2019.12.30.891077
“These results are novel, as only one prior study shows that granulocytic MDSCs produce extracellular DNA (Alfaro et al., 2016).”
Result
The Role of Neutrophil Extracellular Traps (NETs) in the Pathogenesis and Complications of Malignant Diseases
Yuzeir, S., & Gercheva, L. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.93651
“Also, cytokine IL-8, which is frequently expressed by different tumour cells, is described as a NET-inducing factor and has recently been proven to be essential for tumour-induced NETosis [31].”
Background
Venous thromboembolic complications in lymphoma patients
Otašević, V., Antic, D. A., & Mihaljević, B. (2020) · Medicinski podmladak · doi:10.5937/mp71-29196
“Prilikom formiranja tromba, neutrofili su prvi leukociti koji dolaze na mesto povrede krvnog suda, odmah nakon TF. Stimulacija neutrofila različitim faktorima, uključujući aktivirane endotelne ćelije, IL-8, TNF-α i granulocitni faktor rasta (G-CSF), na kraju može da indukuje razvoj NET, u kojeg se poput mreže hvataju…”
Influential
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Pervushin, V. N. (1984) · OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information)
CD4/CD8 Ratio of Pleural Effusion Is A Prognostic Predictor for Non-Small Cell Lung Cancer Patients Under Immune Checkpoint Inhibitor TreatmentsPreprint
Lee, P.-H., Yang, T., Chen, K., Huang, Y.-H., Tseng, J., Hsu, K.-H., Wu, Y., Liu, K., & Chang, G. (2021) · Research Square · doi:10.21203/rs.3.rs-145181/v1
Faculty Opinions recommendation of To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps.
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Immune Gene Therapy of Cancer
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Self-citation
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Additional file 3 of 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., Vulikh, K., Hodge, J. W., Floudas, C. S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728150
Additional file 1 of 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., Vulikh, K., Hodge, J. W., Floudas, C. S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25951855
Additional file 2 of 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., Vulikh, K., Hodge, J. W., Floudas, C. S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25951926
Additional file 4 of 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., Vulikh, K., Hodge, J. W., Floudas, C. S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728153
Additional file 1 of 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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“Similarly, MDSCs can also be recruited by IL-8 [56, 57] and their accumulation and immune inhibitory functions are enhanced by IL-6 [58].”
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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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