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

Authors :
Dawod, Bassel
Liu, Jinghua
Gebremeskel, Simon
Yan, Chi
Sappong, Antonia
Johnston, Brent
Hoskin, David W.
Marshall, Jean S.
Wang, Jun
Source :
Scientific Reports. 8/7/2020, Vol. 10 Issue 1, p1-17. 17p.
Publication Year :
2020

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20452322
Volume :
10
Issue :
1
Database :
Academic Search Index
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
145078239
Full Text :
https://doi.org/10.1038/s41598-020-70231-7