Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors.

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Tumor growth coincides with an accumulation of myeloid-derived suppressor cells (MDSCs), which exert immune suppression and which consist of two main subpopulations, known as monocytic (MO) CD11bEur. J. Immunol. 2013Immunol. . 43: 2930Immunol. -2942 Immunomodulation 2931 IntroductionThe discovery of tumor-specific antigenic peptides recognized by CD8 + T cells has laid the foundation for immunotherapeutic approaches aimed at maximizing cytotoxic T lymphocyte (CTL) mediated eradication of cancer cells. The optimization of such therapies requires a thorough knowledge of the mechanisms regulating CTL induction and activity and of the countermeasures taken by tumors to avoid destruction. Naive CD8 + T cells constantly sample APCs in the secondary lymphoid organs. As a function of this activity, naive T cells express low levels of CD44 and high levels of the homing receptor CD62L, ensuring entry into LNs [1]. Upon activation at these sites, a series of events is initiated that dramatically alters the molecular repertoire of CD8 + T cells, enabling these cells to proliferate, migrate, and acquire effector functions [2]. Importantly, distinct features of CTL activation are obtained in different phases of the activation process and are not necessarily interdependent [3,4]. Thus, a brief DC-T-cell encounter is sufficient to upregulate the early activation markers CD44 and CD69, but longer stable contacts are needed to initiate IL-2 and IFN-γ secretion and the abundant expression of activation markers (including CD25, generating a high-affinity trimeric IL-2R , and IRF-1 −/− C57BL/6 mice bearing similarly sized EG7-OVA tumors. These MDSCs were added in various amounts to OVA-stimulated (250 μg/mL) OT-1 splenocytes and proliferation was measured after 42 h. The percentage suppression induced by various MDSC-SPC ratios is shown as individual replicates, measured via 3 H-thymidine incorporation. Each symbol represents an individual replicate, bars represent means, and data are pooled from two to six independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001; ns, not significant, Mann-Whitney test.be reverted by the iNOS inhibitor L-NG-monomethyl arginine (L-NMMA) ( Fig. 2A(ii)), corroborating the existence of parallel IRF-1/iNOS-dependent and -independent suppressive pathways. This conclusion is strengthened by the partial reduction in suppressive capacity by WT MO-MDSCs upon L-NMMA addition ( Fig. 2A(ii)), and the fact that the NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) could never decrease T-cell proliferation to the same extent as MO-MDSCs despite comparable NO concentrations in the culture ( Fig. 2A(i) and (ii)).Conversely, IFN-γR −/− , STAT-1 −/− , and IRF-1 −/− PMN-MDSCs displayed an NO-independent suppressive capacity, which was moderately, but significantly, lower than WT cells (Fig. 1B and 2B(ii)). Again, IFN-γ −/− PMN-MDSC-mediated suppression was not hampered (data not shown). The relatively minor importance of IFN-γ is not due to a lack of IFN-γ responsiveness, since IFN-γ treatment of PMN-MDSCs u...

The versatility and plasticity of myeloid cell polarization/differentiation has turned out to be crucial in health and disease, and has become the subject of intense investigation during the last years. On one hand, myeloid cells provide a critical contribution to tissue homeostasis and repair. On the other hand, myeloid cells not only play an important role as first line defense against pathogens but also they are involved in a broad array of inflammation-related diseases such as cancer. Recent studies show that macrophages can exist in different activation states within the same tumor, underlining their plasticity and heterogeneity. In this review, we will discuss recent evidence on how the tumor microenvironment, as it evolves, shapes the recruitment, function, polarization and differentiation of the myeloid cell compartment, leading to the selection of myeloid cells with immunosuppressive and angiogenic functions that facilitate tumor progression and dissemination.

Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C– monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C– monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C– monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C– monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C– monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C– monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C– monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C– or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection.