Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs)
Alfaro C (1), Teijeira A (2), Oñate C (3), Perez G (4), Fernandez de Sanmamed M (5), Andueza MP (6), Alignani D (7), Labiano S (8), Azpilikueta A (8), Rodriguez-Paulete A (9), Garasa S (9), Fusco JP (10), Aznar MA (11), Inoges S (9), Medina-Echeverz J (9), Berraondo P (12), Perez-Gracia JL (10), Melero I (13).
(1) Gene Therapy Unit, CIMA.
(2) Oncology, CIMA.
(3) Immunotherapy, CIMA and CUN.
(4) Division of Oncology, clinica Universidad de Navarra. University of Navarra.
(5) Division of Immunology and Immunotherapy, CIMA and Clinica Universidad de Navarra.
(6) Oncology, Clinica Universidad de Navarra.
(7) Hematology, Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA.
(8) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA).
(9) Immunology, CIMA and clinica Universidad de Navarra.
(10) Oncology Department, Clinica Universidad de Navarra. University of Navarra.
(11) Division of Division of Oncology, Center for Applied Medical Research (CIMA, University of Navarra.
(12) Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra.
(13) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA)
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. IL-8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes.
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 IL-8, IL-8 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.
IL-8 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. IL-8 did not modify the T-cell suppressor activity of human MDSC. However, IL-8 induced the formation of NETs in the GrMDSC subset.
IL-8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control.
CITATION Clin Cancer Res. 2016 Mar 8. pii: clincanres.2463.2015.