Amir A. Al-Khami

Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies

Myeloid-derived suppressor cells in tumors, but not in the spleen, activated fatty acid uptake and oxidation (FAO) and increased their immunosuppressive pathways. Blocking FAO with inhibitors induced T-cell–mediated antitumor activity, which provides a novel approach for treatment. 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.

l-Arginine Depletion Blunts Antitumor T-cell Responses by Inducing Myeloid-Derived Suppressor Cells

Enzymatic depletion of the nonessential amino acid l-Arginine (l-Arg) in patients with cancer by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, l-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T cells. Strikingly, we found that peg-Arg I blocked proliferation and cell-cycle progression in normal activated T cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T cells exposed to peg-Arg I. Further mechanistic investigations showed that the addition of citrulline, a metabolic precursor for l-Arg, rescued the antiproliferative effects of peg-Arg I on T cells in vitro. Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo, peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control nonrepressed-2 eIF2α kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the l-Arg-depleting therapy for cancer treatment and suggest a need for cotargeting MDSC in such therapeutic settings.

Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity

Arginine metabolism has been a key catabolic and anabolic process throughout the evolution of the immune response. Accruing evidence indicates that arginine-catabolizing enzymes, mainly nitric oxide synthases and arginases, are closely integrated with the control of immune response under physiological and pathological conditions. Myeloid cells are major players that exploit the regulators of arginine metabolism to mediate diverse, although often opposing, immunological and functional consequences. In this article, we focus on the importance of arginine catabolism by myeloid cells in regulating innate and adaptive immunity. Revisiting this matter could result in novel therapeutic approaches by which the immunoregulatory nodes instructed by arginine metabolism can be targeted.

Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells

ABSTRACT 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.

PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice

The present study establishes poly(ADP-ribose)polymerases (PARPs) role in chronic asthma, demonstrates that it is activated in human asthma, increases the clinical relevance of targeting PARP for blocking or preventing chronic asthma in humans and presents olaparib as a likely candidate drug.

Energy metabolic pathways control the fate and function of myeloid immune cells

The past decade has seen a significant interest in investigating the intracellular metabolism of cells of the immune system. This has increased the realization that immune cells endure metabolic reprogramming upon responding to pathogen‐derived or inflammatory signals. More importantly, not only does this metabolic switch provide for the bioenergetic and biosynthetic demands but also it, in a highly specific manner, determines the cellular fate and function. In this review, we discuss the metabolic aspects that regulate the differentiation and function of myeloid cells, pivotal for both innate and adaptive immunity. The manipulation of these pathways can alter the function of these cells and therefore, could provide novel therapeutic approaches in cancer and other chronic inflammatory conditions.

Metabolic reprogramming of myeloid-derived suppressor cells (MDSC) in cancer.

ABSTRACT MDSC undergo metabolic reprogramming in the tumor resulting in an increased fatty acid β oxidation that supports their immunosuppressive functions. Fatty acid oxidation inhibitors, used to treat coronary disease, significantly delayed tumor growth and had a significantly increased antitumor effect when combined with adoptive cell therapy or low dose chemotherapy.

The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

Malignant cells upregulate distinct energy metabolism programs that support their proliferation, migration, and adaptation to the stressful tumor microenvironment (TME). Additionally, this exaggerated metabolic activity allows cancer cells to hijack essential nutrients and outcompete neighboring infiltrating immune cells, thereby impairing antitumor immunity. During recent years, there has been great interest in the field to understand the tumor-induced energy metabolism signals that regulate the function of immune cells in individuals with cancer. Accordingly, it is now well accepted that uncovering the mechanisms that instruct the metabolic behavior of cancer cells and tumor-associated immune cells is an indispensable strategy for the development of new approaches to overcome immune suppression in tumors. Thus, in this minireview, we briefly discuss the interaction between particular metabolic signaling pathways and immunosuppressive activity in different subsets of myeloid cells within the TME. Additionally, we illustrate potential central mechanisms controlling the metabolic reprogramming of myeloid cells in response to tumor-derived factors.

Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target.

Increasing evidence has shown the close link between energy metabolism and the differentiation, function, and longevity of immune cells. Chronic inflammatory conditions such as parasitic infections and cancer trigger a metabolic reprogramming from the preferential use of glucose to the up‐regulation of fatty acid oxidation (FAO) in myeloid cells, including macrophages and granulocytic and monocytic myeloid‐derived suppressor cells. Asthma is a chronic inflammatory condition where macrophages, eosinophils, and polymorphonuclear cells play an important role in its pathophysiology.