Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas

• Published in: Scientific reports 2020-08, Vol.10 (1), p.13343-13343, Article 13343
• Main Authors: Dawod, Bassel, Liu, Jinghua, Gebremeskel, Simon, Yan, Chi, Sappong, Antonia, Johnston, Brent, Hoskin, David W., Marshall, Jean S., Wang, Jun
• Format: Article
• Language: English
• Subjects: 631/250/127/1213; 631/250/2161; 631/67/1347; 631/67/327; 631/67/70; Animals; B-Lymphocytes - metabolism; Breast cancer; Breast carcinoma; Breast Neoplasms - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cell Proliferation - physiology; Female; Granulocyte colony-stimulating factor; Humanities and Social Sciences; Humans; Immune response; Inflammation; Interleukin 23; Interleukin-17 - metabolism; Invasiveness; Killer Cells, Natural - metabolism; Leukocytes; Lipopolysaccharides; Lung Neoplasms - metabolism; Lymphocytes B; Lymphocytes T; Mammary gland; Mammary Neoplasms, Experimental - metabolism; Metastases; Metastasis; Mice; Mice, Inbred BALB C; mRNA; multidisciplinary; Myeloid Cells - metabolism; Myeloid-Derived Suppressor Cells - metabolism; Peripheral blood; Plasma levels; Science; Science (multidisciplinary); Suppressor cells; Triple Negative Breast Neoplasms - metabolism; Tumors; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70231-7

Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine that has both pro- and anti-tumor effects and found in 40–80% of TNBC samples. We report here that IL-17A mRNA and protein are detectable in some human TNBC cell lines and further upregulated by IL-23 and LPS stimulation. Furthermore, the impact of tumor-derived IL-17A in host immune response and tumor growth was examined using murine TNBC 4T1 mammary carcinoma cells transduced with an adenoviral vector expressing IL-17A (AdIL-17A) or control vector (Addl). Compared to Addl-transduction, AdIL-17A-transduction enhanced 4T1 tumor growth and lung metastasis in vivo, which was associated with a marked expansion of myeloid-derived suppressor cells (MDSCs). However, AdIL-17A-transduction also induced strong organ-specific and time-dependent immune activation indicated by dynamic changes of NK cells, B cells, CD4, and CD8 T cells in peripheral blood, lung, and tumor site, as well as the plasma levels of IFNγ. Such findings highlight that tumor-associated IL-17A induces concurrent immune activation and immune suppression. Administration of anti-Gr1 or anti-G-CSF antibody effectively depleted MDSCs in vivo, markedly reducing the growth of AdIL-17A-transduced 4T1 tumors, and eliminating lung metastasis. Collectively, our study demonstrates that MDSC depletion is an effective and practical approach for treating IL-17A-enriched mammary carcinomas.