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

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.

Dendritic Cells and Myeloid Derived Suppressor Cells Fully Responsive to Stimulation via Toll-Like Receptor 4 Are Rapidly Induced from Bone-Marrow Cells by Granulocyte-Macrophage Colony-Stimulating Factor

“…Their phenotype and functions have been studied in detail only more recently [31,32]. Whilst some studies use CD11b+, GR-1+ phenotype to describe MDSCs in different disease models [33][34][35], others define granulocytic MDSCs as Ly6Ghi and monocytic MDSCs as Ly6Chi [36,37]. Here it is shown that GR-1 hi MDSCs are morphologically granulocytic, confirmed by their expression of Ly6G, and GR-1 int MDSCs are monocytic like cells morphologically and express high levels of Ly6C.…”

Modeling the Th17 and Tregs Paradigm: Implications for Cancer Immunotherapy

“…Factors such as the inherent variability of cancer and the complexity of the TME make it very difficult to detect a viable and reproducible metabolic fingerprint, especially when considering how certain components of the TME, such as Th17 cells and other subsets with IL-17 and IL-23, can help both fight (Muranski et al, 2008) and promote cancer growth (Numasaki et al, 2005;Dawod et al, 2020), but it is also notable that positive results have been achieved recently during attempts to find biomarkers of chemotherapeutic responses (Cardoso et al, 2018;Amin et al, 2019;Ghini et al, 2020). Biomarkers for response to immune checkpoint inhibitor therapy (ICI), such as the ratio of serum kynurenine/tryptophan, have shown promise in detecting negative outcomes for treatment in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programed cell death protein 1 (PD1) (Li H. et al, 2019).…”

A Mechanistic Insight into the Pathogenic Role of Interleukin 17A in Systemic Autoimmune Diseases

“…Several of these immune properties of IL-17A have been recapitulated in autoinflammatory disorders and more recently cancer, and on top of that, new features have been uncovered [ 17 , 18 ]. As for the latter, IL-17A assists in shaping the tumor microenvironment by dampening tumor-specific immune responses involving proangiogenic signals, progressive loss of antitumor Th1 immunity, and suppression of T cell immune surveillance [ 19 , 20 ]. In addition, IL-17A has been shown to promote protumorigenic factors like proliferation capacity, immune cell infiltration, resistance to chemotoxicity, and migratory and invasive properties [ 19 – 26 ].…”