Interferon regulatory factor‐8 modulates the development of tumour‐induced CD11b⁺Gr‐1⁺ myeloid cells

Abstract

Tumor-induced myeloid-derived suppressor cells (MDSC) promote immune suppression and mediate tumor progression. However, the molecular basis for the generation of MDSC, which in mice co-express the CD11b+ and Gr-1+ cell surface markers remains unclear. Because CD11b+Gr-1+ cells expand during progressive tumor growth, this suggests that tumor-induced events alter signaling pathways that affect normal myeloid cell development. Interferon regulatory factor-8 (IRF-8), a member of the IFN-γ regulatory factor family, is essential for normal myelopoiesis. We therefore examined whether IRF-8 modulated tumor-induced CD11b+Gr-1+ cell development or accumulation using both implantable (4T1) and transgenic (MMTV-PyMT) mouse models of mammary tumor growth. In the 4T1 model, both splenic and bone marrow-derived CD11b+Gr-1+ cells of tumor-bearing mice displayed a marked reduction in IRF-8 expression compared to control populations. A causal link between IRF-8 expression and the emergence of tumor-induced CD11b+Gr-1+ cells was explored in vivo using a double transgenic (dTg) mouse model designed to express transgenes for both IRF-8 and mammary carcinoma development. Despite the fact that tumor growth was unaffected, splenomegaly, as well as the frequencies and absolute numbers of CD11b+Gr-1+ cells were significantly lower in dTg mice when compared with single transgenic tumor-bearing mice. Overall, these data reveal that IRF-8 plays an important role in tumor-induced development and/or accumulation of CD11b+Gr-1+ cells, and establishes a molecular basis for the potential manipulation of these myeloid populations for cancer therapy.

Polarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus Infection

“…Our findings clearly show that HBsAg induces the development of mMDSCs via IL-6. Signaling molecules, including ERK1/2, p38 MAPK, and the STAT3, IFN regulatory factor 8, and NF-kB transcription factors, have been implicated in the regulation of MDSC differentiation in cancers (20,21). We revealed that the HBsAg-activated ERK MAPK pathway induces IL-6 production, whereas the inhibition of ERK phosphorylation blocks the development of mMDSCs.…”

“…Our results clearly demonstrate that IL-6 induced by HBsAg contributes in an autocrine manner to the induction of mMDSCs. MAPKs and NF-kB have been shown to regulate cytokine production in monocytes (20)(21)(22). To investigate the molecular mechanism of IL-6 production in HBsAg-treated monocytes, we evaluated the phosphorylation of ERK1/2 MAPK and the degradation of IkBa.…”

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

“…ϩ MDSC-like cells (40,45,46); we then examined spontaneous apoptosis of spleen CD11b ϩ Gr1 ϩ cells from IRF8 KO and WT control mice. MDSC-like cells from IRF8 KO mice exhibited significantly less spontaneous apoptosis as compared with WT mice (Fig.…”

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

“…STAT3 can regulate arginase production by binding directly to the ARG1 promoter (60). The effect of STAT3 on MDSC accumulation and suppressive function was found to be mediated by C/EBPβ (55) and IFN regulatory factor-8 (IRF8) (61,62). Pharmacological inhibition of STAT3 in MDSCs favored their conversion toward mature DCs, in part through inhibition of PKCβII (63).…”