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IL-8

Diagram of IL-8 pathway between MCSCs and tumor cells

Interleukin-8 (IL-8) can recruit immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and promote angiogenesis and tumor metastasis. Inhibition of IL-8 may reduce these tumorigenic effects.

Expression and normal function

Interleukin-8 (IL-8) is a cytokine produced by macrophages, monocytes, and stromal cells¹

IL-8 binds to G protein–coupled receptors chemokine (C-X-C motif) receptor 1 (CXCR1) and 2 (CXCR2) and promotes the recruitment of immunosuppressive MDSCs^2,3

During the normal healing process, IL-8 also activates the angiogenic response to generate new blood vessels⁴

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Role in cancer

Both tumor and tumor-associated stromal cells can upregulate production of IL-8, causing MDSCs to migrate to the tumor microenvironment where they suppress the antitumor immune response and expand the stroma^2,4-7

The stroma may act as a barrier to prevent immune recognition and subsequent T-cell infiltration^8,9

In addition, tumor-derived IL-8 acts as a potent factor that promotes both angiogenesis and tumor metastasis^4,10

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Preclinical evidence

Elevated IL-8 levels are associated with poor prognoses in a wide range of tumor types^11,12
Preclinical studies suggest that blockade of IL-8 signaling reduces both the recruitment of CXCR1- and CXCR2-expressing MDSCs to the stromal barrier and tumor microenvironment, and angiogenesis^2,10,13

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REFERENCES–IL-8

1. Duque GA, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. doi:10.3389/fimmu.2014.00491. 2. Alfaro C, Teijeira A, Oñate C, et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res. 2016;22(15):3924-3936. 3. Waugh DJJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14(21):6735-6741. 4. David JM, Dominguez C, Hamilton DH, Palena C. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel). 2016;4(3). doi:10.3390/vaccines4030022. 5. Katanov C, Lerrer S, Liubomirski Y, et al. Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway. Stem Cell Res Ther. 2015;6:87. doi:10.1186/s13287-015-0080-7. 6. Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Adenan NAM, Chung I. Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. PLoS ONE. 2013;8(7):e68923. doi:10.1371/journal.pone.0068923. 7. Asfaha S, Dubeykovskiy AN, Tomita H, et al. Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis. Gastroenterology. 2013;144(1):155-166. 8. Salmon H, Donnadieu E. Within tumors, interactions between T cells and tumor cells are impeded by the extracellular matrix. Oncoimmunology. 2012;1(6):992-994. 9. Spiotto MT, Yu P, Rowley DA, et al. Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity. 2002;17(6):737-747. 10. Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol. 2002;161(1):125-134. 11. Fujita Y, Okamoto M, Goda H, et al. Prognostic significance of interleukin-8 and CD163-positive cell-infiltration in tumor tissues in patients with oral squamous cell carcinoma. PLoS ONE. 2014;9(12):e110378. doi:10.1371/journal.pone.0110378. 12. Sanmamed MF, Carranza-Rua O, Alfaro C, et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res. 2014;20(22):5697-5707. 13. Wu S, Shang H, Cui L, et al. Targeted blockade of interleukin-8 abrogates its promotion of cervical cancer growth and metastasis. Mol Cell Biochem. 2013;375(1-2):69-79.