Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer
Charli Dominguez, Kristen K. McCampbell, Justin M. David, Claudia Palena
Charli Dominguez, Kristen K. McCampbell, Justin M. David, Claudia Palena
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Research Article Immunology Oncology

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

Abstract

The complex signaling networks of the tumor microenvironment that facilitate tumor growth and progression toward metastatic disease are becoming a focus of potential therapeutic options. The chemokine IL-8 is overexpressed in multiple cancer types, including triple-negative breast cancer (TNBC), where it promotes the acquisition of mesenchymal features, stemness, resistance to therapies, and the recruitment of immune-suppressive cells to the tumor site. The present study explores the utility of a clinical-stage monoclonal antibody that neutralizes IL-8 (HuMax-IL8) as a potential therapeutic option for TNBC. HuMax-IL8 was shown to revert mesenchymalization in claudin-low TNBC models both in vitro and in vivo as well as to significantly decrease the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) at the tumor site, an effect substantiated when used in combination with docetaxel. In addition, HuMax-IL8 enhanced the susceptibility of claudin-low breast cancer cells to immune-mediated lysis with NK and antigen-specific T cells in vitro. These results demonstrate the multifaceted way in which neutralizing this single chemokine reverts mesenchymalization, decreases recruitment of MDSCs at the tumor site, assists in immune-mediated killing, and forms the rationale for using HuMax-IL8 in combination with chemotherapy or immune-based therapies for the treatment of TNBC.

Authors

Charli Dominguez, Kristen K. McCampbell, Justin M. David, Claudia Palena

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Figure 4

Neutralization of IL-8 reduces chemotaxis of murine CD11b+ cells.

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Neutralization of IL-8 reduces chemotaxis of murine CD11b+ cells. (A) Ce...
(A) Cell counts of murine CD11b+ chemotaxis induced via media containing IgG (25 μg/ml) or HuMax-IL8 (25 μg/ml), with or without addition of recombinant human IL-8 (100 ng/ml). Data represent mean (bars) + SEM (error bars) from n = 3 (dots); differences between means were compared using 1-way ANOVA with Tukey’s multiple comparisons test; ***P < 0.001. Data are representative of 3 experiments. (B) Chemotaxis of murine CD11b+ cells in response to cultured media obtained from MDA-MB-231 cells pretreated with IgG or HuMax-IL8. Data represent mean (bars) + SEM (error bars) from n = 4 (dots); differences between means were compared using a 2-tailed unpaired t test; ***P < 0.001. Data are representative of 2 experiments.