Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell–dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. Cancer Immunol Res; 3(11); 1236–47. ©2015 AACR.

Myeloid-derived suppressor cells (MDSC) promote tumor growth by blocking anti-tumor T cell responses. Recent reports show that MDSC increase fatty acid uptake and fatty acid oxidation (FAO) to support their immunosuppressive functions. Inhibition of FAO promoted a therapeutic T cell-mediated anti-tumor effect. Here, we sought to determine the mechanisms by which tumor-infiltrating MDSC increase the uptake of exogenous lipids and undergo metabolic and functional reprogramming to become highly immunosuppressive cells. The results showed that tumor-derived cytokines (G-CSF and GM-CSF) and the subsequent signaling through STAT3 and STAT5 induce the expression of lipid transport receptors with the resulting increase in the uptake of lipids present at high concentrations in the tumor microenvironment. The intracellular accumulation of lipids increases the oxidative metabolism and activates the immunosuppressive mechanisms. Inhibition of STAT3 or STAT5 signaling or genetic depletion of the fatty acid translocase CD36 inhibits the activation of oxidative metabolism and the induction of immunosuppressive function in tumor-infiltrating MDSC and results in a CD8⁺ T cell-dependent delay in tumor growth. Of note, human tumor-infiltrating and peripheral blood MDSC also upregulate the expression of lipid transport proteins, and lipids promote the generation of highly suppressive human MDSC in vitro. Our data therefore provide a mechanism by which tumor-derived factors and the high lipid content in the tumor microenvironment can cause the profound metabolic and functional changes found in MDSC and suggest novel approaches to prevent or reverse these processes. These results could further enhance the efficacy of cancer immunotherapy.

The single-stranded DNA- and RNA-binding protein, Purα, has been implicated in many biological processes, including control of transcription of multiple genes, initiation of DNA replication, and RNA transport and translation. Deletions of the PURA gene are frequent in acute myeloid leukemia. Mice with targeted disruption of the PURA gene in both alleles appear normal at birth, but at 2 weeks of age, they develop neurological problems manifest by severe tremor and spontaneous seizures and they die by 4 weeks. There are severely lower numbers of neurons in regions of the hippocampus and cerebellum of PURA^−/− mice versus those of age-matched +/+ littermates, and lamination of these regions is aberrant at time of death. Immunohistochemical analysis of MCM7, a protein marker for DNA replication, reveals a lack of proliferation of precursor cells in these regions in the PURA^−/− mice. Levels of proliferation were also absent or low in several other tissues of the PURA^−/− mice, including those of myeloid lineage, whereas those of PURA^+/− mice were intermediate. Evaluation of brain sections indicates a reduction in myelin and glial fibrillary acidic protein labeling in oligodendrocytes and astrocytes, respectively, indicating pathological development of these cells. At postnatal day 5, a critical time for cerebellar development, Purα and Cdk5 were both at peak levels in bodies and dendrites of Purkinje cells of PURA^+/+ mice, but both were absent in dendrites of PURA^−/− mice. Purα and Cdk5 can be coimmunoprecipitated from brain lysates of PURA^+/+ mice. Immunohistochemical studies reveal a dramatic reduction in the level of both phosphorylated and nonphosphorylated neurofilaments in dendrites of the Purkinje cell layer and of synapse formation in the hippocampus. Overall results are consistent with a role for Purα in developmentally timed DNA replication in specific cell types and also point to a newly emerging role in compartmentalized RNA transport and translation in neuronal dendrites.

The broad range of histological lesions associated with HIV‐1 are somewhat subtle relative to the clinical manifestations that occur as a result of HIV infection. Although it is clear that HIV has a causative role in CNS disease, dementia appears to be a consequence of the infiltration of inflammatory cells and cytokine dysregulation rather than the amount of virus in CNS. The HIV transregulatory protein Tat plays an important intracellular as well as extracellular role in the dysregulation of cytokines. The cytokines and possibly chemokines that are induced by Tat modify the action of astrocytes such that the survival of neurons is compromised. Pathogenetic alteration induced by Tat involves a series of interactions between circulating monocyte/macrophages, endothelial cells, and astrocytes. Cytokine dysregulation induced by viral infection and extracellular Tat leads to alterations in expression of adhesion molecules and promotes migration of non‐infected inflammatory cells into the CNS compartment. We demonstrate here that recombinant HIV‐1 Tat protein introduced by stereotaxic injection into mouse brain can induce pathologically relevant alterations including macrophage invasion as well as astrocytosis. The mechanism of destruction of the CNS by Tat appears to involve autocrine and paracrine pathways that depend not only on Tat, but cytokine and chemokine signaling pathways that are altered by viral infection. In this review, we discuss various pathogenic effects of Tat in brain cells and provide experimental evidence for an increased TNF‐α level in CSF in mice injected intracerebrally with Tat protein. J. Leukoc. Biol. 65: 458–465; 1999.