Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system.

Coordinated regulation of myeloid cells by tumours

The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.

Natural Innate and Adaptive Immunity to Cancer

https://www.cell.com/trends/immunology/pdf/S1471-4906(16)00005-3.pdf

The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.

The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-CELL suppressive activity

The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases.

Immunology in the liver — from homeostasis to disease

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules However, lipid-laden DCs had a reduced capacity to process antigens Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs

/pdf/lipid-accumulation-and-dendritic-cell-dysfunction-in-cancer-2dgsp3034d.pdf

Lipid accumulation and dendritic cell dysfunction in cancer

Neutrophils and Myeloid-Derived Suppressor Cells in Cancer

Nitrogen and oxygen are essential for sustaining life on earth. They are not only part of the amino acids and the nucleotides, but also critical for energy transfer in cells. The majority of living organisms have taken advantage of the availability of oxygen, and their existence has become dependent on the presence of this element at all times. At the cellular level, oxygen is necessary for the generation of energy during the aerobic respiration process which occurs in mitochondria. Oxygen is invariably used as the terminal electron acceptor. High-energy electrons from nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) are ultimately transferred to oxygen via various electron carriers in the inner mitochondrial membrane and, in the process, a proton gradient is created that drives the synthesis of ATP. The high electronegativity of O2 enables aerobic organisms to produce much higher amounts of ATP than anaerobic organisms. However, this efficiency comes with the price of the generation of toxic-free radicals via the reduction of O2 to free radical superoxide (O.− 2 ), which happens primarily within the mitochondria. In fact, it has been speculated that 1–2 % of daily consumed oxygen is converted to O.− 2 by mitochondrial respiration. The generation of O.− 2 if uncontrolled can become a predicament because of up to nine of the various mitochondrial enzymes and redox carriers having been reported as possible O.− 2 producing sites (Andreyev et al., 2005). Reactive oxygen species (ROS) are produced in response to multiple stimuli. Even immunoglobulins and the T-cell receptor contain a catalytic site that promotes the formation of ROS (Datta et al., 2002). ROS are a crucial component of many immunological reactions and their significant role in biology and cancer is just now being fully acknowledged. In this review we will focus on the importance of oxygen for normal leukocyte biology and how oxygen metabolites are manipulated by cancer to inhibit T-cell functions and allow the progression of the disease.

Role of Reactive Oxygen Species in T-Cell Defects in Cancer

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Lipid accumulation and dendritic cell dysfunction in cancer

Neutrophils and Myeloid-Derived Suppressor Cells in Cancer

Role of Reactive Oxygen Species in T-Cell Defects in Cancer