The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies

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The cancer metabolic reprogramming and immune response.

Hypertensive heart disease.

In recent years, an increasingly more in depth understanding of tumor metabolism in tumorigenesis, tumor growth, metastasis, and prognosis has been achieved. The broad heterogeneity in tumor tissue is the critical factor affecting the outcome of tumor treatment. Metabolic heterogeneity is not only found in tumor cells but also in their surrounding immune and stromal cells; for example, many suppressor cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and tumor-associated T-lymphocytes. Abnormalities in metabolism often lead to short survival or resistance to antitumor therapy, e.g., chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Using the metabolic characteristics of the tumor microenvironment to identify and treat cancer has become a great research hotspot. This review systematically addresses the impacts of metabolism on tumor cells and effector cells and represents recent research advances of metabolic effects on other cells in the tumor microenvironment. Finally, we introduce some applications of metabolic features in clinical oncology.

/pdf/effects-of-glucose-metabolism-lipid-metabolism-and-glutamine-sx69etl7.pdf

Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications

Prolonged pressure overload triggers cardiac hypertrophy and frequently leads to heart failure (HF). Vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 are components of the central pathway for lymphatic vessel growth (also known as lymphangiogenesis), which has crucial functions in the maintenance of tissue fluid balance and myocardial function after ischemic injury. However, the roles of this pathway in the development of cardiac hypertrophy and dysfunction during pressure overload remain largely unknown. Eight- to 10-week-old male wild-type (WT) mice, VEGFR-3 knockdown (VEGFR-3f/- ) mice, and their WT littermates (VEGFR-3f/f ) were subjected to pressure overload induced by transverse aortic constriction (TAC) for 1-6 weeks. We found that cardiac lymphangiogenesis and the protein expression of VEGF-C and VEGFR-3 were upregulated in the early stage of cardiac hypertrophy but were markedly reduced in failing hearts. Moreover, TAC for 6 weeks significantly reduced cardiac lymphangiogenesis by inhibiting activation of VEGFR-3-mediated signals (AKT/ERK1/2, calcineurin A/NFATc1/FOXc2, and CX43), leading to increased cardiac edema, hypertrophy, fibrosis, apoptosis, inflammation, and dysfunction. These effects were further aggravated in VEGFR-3f/- mice and were dose-dependently attenuated by delivery of recombinant VEGF-C156S in WT mice. VEGF-C156s administration also reversed pre-established cardiac dysfunction induced by sustained pressure overload. Thus, these results demonstrate, for the first time, that activation of the VEGF-C-VEGFR-3 axis exerts a protective effect during the transition from cardiac hypertrophy to HF and highlight selective stimulation of cardiac lymphangiogenesis as a potential new therapeutic approach for hypertrophic heart diseases.

VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis.

In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the post-MI cardiac function of mice in which lymphangiogenesis had been blocked genetically by pan-endothelial or lymphatic endothelial loss of the lymphangiogenic receptor VEGFR3 or global loss of the VEGF-C and VEGF-D ligands. The results obtained using all three genetic approaches were highly concordant and demonstrated that loss of lymphatic vessel growth did not impair left ventricular ejection fraction two weeks after MI in mice. We observed a trend toward excess fluid in the infarcted region of the left ventricle, but immune cell infiltration and clearance were unchanged with loss of expanded lymphatics. These studies refute the hypothesis that lymphangiogenesis contributes significantly to cardiac function after MI, and suggest that any effect of exogenous VEGF-C is likely to be mediated by non-lymphangiogenic mechanisms.

/pdf/genetic-blockade-of-lymphangiogenesis-does-not-impair-269p0bkrr2.pdf

Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction

The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell populations revealed that VEGFCc156s specifically modulated angiotensin II-induced inflammatory responses in cardiac and peripheral lymphatic endothelial cells. Furthermore, telemetry studies showed that while angiotensin II increased blood pressure acutely in all animals, VEGFCc156s-treated animals displayed a delayed systemic reduction in blood pressure independent of alterations in angiotensin II-mediated aortic stiffness. Overall, these results demonstrate that VEGFCc156s had a multifaceted therapeutic effect to prevent angiotensin II-induced cardiac dysfunction by improving cardiac lymphatic function, alleviating fibrosis and inflammation, and ameliorating hypertension.

/pdf/lymphangiogenic-therapy-prevents-cardiac-dysfunction-by-mpqiilrh6o.pdf

Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation-induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4+ T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.

Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4+ T Cell Effector Functions and Activation-Induced Metabolic Reprogramming.

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Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4+ T Cell Effector Functions and Activation-Induced Metabolic Reprogramming.