Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

Abstract

Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (T H 1) was significantly attenuated, and impaired T H 1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Furthermore, we found that Gr-1 þ myeloid-derived suppressor cells (MDSC) served as a source of IL-6 in tumor-bearing mice. Adoptive transfer of effector CD4 þ T cells revealed that MDSC-sensitized effector CD4 þ T cells were less potent in mounting antitumor immune responses, although effector T cells generated together with Gr-1 þ cells from tumor-free mice eradicated established tumors. CD8 þ T cells, IFN-g, and MHC-class II expression in host mice were indispensable for the antitumor activity initiated by effector CD4 þ T cells. Despite comparable suppressive activity of IL-6 þ/þ and IL-6 À/À MDSC on primary T-cell activation, transfer of IL-6 þ/þ MDSC, but not IL-6 À/À MDSC, dampened the efficient induction of effector T H 1 cells and counteracted CD4 þ T cell-mediated antitumor immunity including cognate help for CD8 þ T cells in vivo. These findings suggest that, apart from the inhibitory effects on primary T-cell activation, MDSC promote tumor progression by attenuating functional differentiation of tumor-specific CD4 þ T cells into effector T H 1 cells through IL-6 production to promote tumor progression. This novel mode of MDSC-induced tolerance of effector CD4 þ T cells should be considered as the basis for the rational design of effective T cell-mediated antitumor therapies.

Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

“…Although CD8 + T cells are important in tumor clearance, they are not the only cell involved 75 . MDSCs have been reported to have inhibitory effects on several immune effector cell types including NK cells 18,19 and CD4 + T cells 76,77 directly, 21 or via inhibition of DC function 20 or induction of regulatory T cell development 78 . In addition, antibody-mediated processes such as complement mediated lysis and antibody-dependent cell-mediated cytotoxicity can also be affected by MDSCs.…”

Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression

“…Tumor size is expressed as tumor index, which is the square root of (length  width) as described previously (7). In the pulmonary metastatic model, mice were intravenously injected with 5  10 5 OVA/firefly luciferase-expressing melanoma, MO4-Luc (7).…”

“…While the induction of tumor-specific CD8 þ T cells has been the main focus in cancer immunotherapy, recent studies have suggested that the better prognosis is correlated with higher levels of IFNg-expressing CD4 þ T (Th1) cells in patients with cancer, implying an important role of Th1 cells in controlling tumor regression (3)(4)(5). However, Th1 responses tend to be abolished in patients with cancer (3,5) and tumor-bearing animals (6,7). An induction of tolerance against immunosurveillance in tumor microenvironment is suggested to be the cause for failure of tumor-specific T cells to eradicate malignant cells (1,3,6).…”

“…We have previously shown that priming of tumor-specific CD4 þ T cells in combination with a treatment of anti-IL6 blocking Ab enhanced the antitumor CD4 þ T-cell responses (7). However, the mechanistic action by which IL6 attenuates the T-cell-mediated antitumor responses remains to be elucidated.…”

Dual role of inflammatory mediators in cancer

“…Myeloid-derived suppressor cells secrete IL-10, IL-6, TNF-Alfa, IL-1 beta, COX-2, IFN-Gama,HIF-1 Alfa and ROS, skew the CD4+ T Cells to Tregs and suppress the antitumour immunity of CD4+, CD8+, and NK cells, resulting in the suppressive and tolerogenic environment and M2 phenotypic polarisation of tumour-associated macrophages favouring tumour progression. MDSC mediated cellular proliferation, angiogenesis by activation of STAT-3, invasion by MMP through degradation of the extracellular matrix or basement membrane and epithelial to mesenchymal transition by secretion of TGF-Beta, HGF, and FGF [16, 17, 27, 28]. …”