Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response

Abstract

Although the immune system has the potential to protect against malignancies, many individuals with cancer are immunosuppressed. Myeloid-derived suppressor cells (MDSC) are elevated in many patients and animals with tumors, and contribute to immune suppression by blocking CD4+ and CD8+ T cell activation. Using the spontaneously metastatic 4T1 mouse mammary carcinoma, we now demonstrate that cross-talk between MDSC and macrophages further subverts tumor immunity by increasing MDSC production of IL-10, and by decreasing macrophage production of IL-12. Cross-talk between MDSC and macrophages requires cell-cell contact, and the IL-12 decrease is dependent on MDSC production of IL-10. Treatment with the chemotherapeutic drug gemcitabine, which reduces MDSC, promotes rejection of established metastatic disease in IL-4Rα−/− mice that produce M1 macrophages by allowing T cell activation, by maintaining macrophage production of IL-12, and by preventing increased production of IL-10. Therefore, MDSC impair tumor immunity by suppressing T cell activation and by interacting with macrophages to increase IL-10 and decrease IL-12 production, thereby promoting a tumor-promoting type 2 response, a process that can be partially reversed by gemcitabine.

Convergent pathways of macrophage polarization: The role of B cells

“…Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the In a model of mammary carcinoma, myeloid-derived suppressor cells were shown to contribute to tumor progression by suppressing T-cell activation and inducing an M2-like phenotype of TAM, (increased IL-10 and decreased IL-12 production) [10].The role of B cells in solid tumor development is well characterized, for example B-cell-deficient mice (mMT) exhibited resistance to several type of syngeneic tumors, including EL4 lymphoma, MC38 colon carcinoma and B16 or D5 melanoma [9]. A first original report on B cells and cancer progression, in a transgenic mouse model of inflammation-associated cancer (HPV16 mice), demonstrated the importance of B cells in de novo epithelial carcinogenesis [11].…”

“…Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the In a model of mammary carcinoma, myeloid-derived suppressor cells were shown to contribute to tumor progression by suppressing T-cell activation and inducing an M2-like phenotype of TAM, (increased IL-10 and decreased IL-12 production) [10].…”

“…In a model of mammary carcinoma, myeloid-derived suppressor cells were shown to contribute to tumor progression by suppressing T-cell activation and inducing an M2-like phenotype of TAM, (increased IL-10 and decreased IL-12 production) [10].…”

Phenotypic and functional dissection of myeloid-derived suppressor cells

“…In turn, MDSCs suppress the proliferation of T cells effectively, because arginine is a key nutritional substrate for T cell proliferation Munder 2009;Rodriguez et al 2009). MDSCs also secret immunosuppressive cytokine IL-10, which leads to immunosuppressive regulatory T cells (Treg) activation as well as the induction of the anti-inflammatory M2 macrophage differentiation, and the expansion of MDSC population by tumor growth contribute to immune escape of tumor cells through these suppressive effects of IL-10 (Sinha et al 2007;Heim et al 2015). Besides of these common suppressive mechanism including arginase expression and IL-10 secretion, G-MDSCs tend to primarily use ROS as the mechanism for immune suppression (Kusmartsev et al 2004;Sinha et al 2005;Nagaraj et al 2007;Nefedova et al 2007;Ando et al 2008;Markiewski et al 2008;Youn et al 2008;Corzo et al 2009).…”

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

“…Next, the cells were stained with either 0.25 mg PElabeled anti-IFN-c (GIR-208), IL-4 (11B11), IL-10 (JES5-16E3), IL-12 (C17.8), TNF-a (MP6-XT22) or IL-17A (eBio17B7) mAb for 30 min at room temperature in the dark and washed three times, and 10 000 F4/ 80 1 cells were then analyzed by FCM. 26,28,29 Arginase assay The arginase activity assay was performed as previously described. 30,31 Briefly, the cells were lysed in 0.1% Triton X-100.…”