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 7

Immune-mediated lysis is enhanced with blockade of IL-8 in vitro.

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Immune-mediated lysis is enhanced with blockade of IL-8 in vitro. (A) Ly...
(A) Lysis of indicated tumor cell lines mediated by NK cells purified from blood of 2–3 healthy donors, following tumor cell treatment with HuMax-IL8 versus control IgG for 3 days. Data represent mean (bars) + SEM (error bars), n = 3 (dots); difference between means was assessed with 2-tailed t test for each TNBC cell line. Data are representative of 3 experiments. (B) Susceptibility of MDA-MB-231 cells treated with control HuMax-IL8 versus control IgG to lysis by MUC-1-, CEA-, and brachyury-specific CD8+ T cells. Data represent mean (bars) + SEM (error bars), n = 3–4 (dots); difference between means was assessed with 2-tailed t test for each antigen-specific T cell line. Data are representative of 2 experiments. (C) NK- and TRAIL-mediated lysis of MDA-MB-231, Hs578T, and MDA-MB-436 cells that were untreated or pretreated with the pan-caspase inhibitor Z-VAD-FMK prior to the cytotoxic assay. Data represent mean (bars) ± SEM (error bars), n = 3–4 (dots); differences between means were compared with 1-way ANOVA test with Tukey’s multiple comparisons. Data are from 1 experiment. (D) CEA- and MUC-1-specific CD8+ T cells were left untreated or pretreated with CMA for blockade of granzyme/perforin activity and utilized for lysis with MDA-MB-231 and BT549 target cells treated with HuMax-IL8 versus control IgG. Data represent mean (bars) ± SEM (error bars), n = 3 (dots); differences between means were compared with 1-way ANOVA test with Tukey’s multiple comparisons. Data are representative of 2 experiments. *P < 0.05; **P < 0.01; ***P < 0.001.