Metabolic Checkpoints: Novel Avenues for Immunotherapy of Cancer

Novel therapies targeting immune checkpoint molecules have redefined the treatment of cancer at advanced stages and brought hope to millions of patients worldwide. Monoclonal antibodies targeting immune-inhibitory receptors often lead to complete and objective responses as well as to durable progression-free survival where all other therapeutic approaches fail. Yet, many tumors show significant resistance to checkpoint blockade through mechanisms that are only starting to come to light. An alluring alternative strategy to reinvigorate anticancer immune responses comes from the emerging field of immuno-metabolism. Over the past few years, numerous studies revealed that many well-known metabolic playmakers also serve as critical checkpoints in immune homeostasis and immunity against tumors. Here, we survey recent insights into the intimate and intertwining links between T cell metabolic programs and environmental cues in the tumor milieu. Transferring these new findings from the bench to the bedside may soon entirely re-shape the field of cancer immunotherapy and significantly improve the lives of patients

Interferon-α Up-Regulates the Expression of PD-L1 Molecules on Immune Cells Through STAT3 and p38 Signaling

Interferon-α (IFNα) has one of the longest histories of use amongst cytokines in clinical oncology and has been applied for the treatment of many types of cancers. Due to its immune-activating properties, IFNα is also an attractive candidate for combinatory anti-cancer therapies. Despite its extensive use in animal tumor models as well as in several clinical trials, the different mechanisms underlying patient responses and affecting desirable clinical benefits are still under investigation. Here we show that in addition to its immune-activating properties, IFNα induces the expression of a key negative regulator, immunosuppressive PD-L1 molecule, in the majority of the specific immune cell populations, particularly in the dendritic cells (DC). DC can modulate immune responses by a variety of mechanisms, including expression of T-cell regulatory molecules and cytokines. Our results showed that treatment of DC with IFNα-2b led to pronounced up-regulation of surface expression of PD-L1 molecules, increased IL-6 and decreased IL-12 production. Moreover, we present evidence that IFNα-treated DC exhibited a reduced capacity to stimulate interferon-γ production in T cells compared to control DC. This T-cell response after treatment of DC with IFNα was recovered by a pre-treatment with an anti-PD-L1 blocking antibody. Further analyses revealed that IFNα regulated PD-L1 expression through the STAT3 and p38 signaling pathways, since blocking of STAT3 and p38 activation with specific inhibitors prevented PD-L1 up-regulation. Our findings underline the important roles of p38 and STAT3 in the regulation of PD-L1 expression and prove that IFNα induces STAT3/p38-mediated expression of PD-L1 and thereby a reduced stimulatory ability of DC. The augmentation of PD-L1 expression in immune cells through IFNα treatment should be considered by use of IFNα in an anti-cancer therapy

The Importance of Cellular Metabolic Pathways in Pathogenesis and Selective Treatments of Hematological Malignancies

Despite recent advancements in the treatment of hematologic malignancies and the emergence of newer and more sophisticated therapeutic approaches such as immunotherapy, long-term overall survival remains unsatisfactory. Metabolic alteration, as an important hallmark of cancer cells, not only contributes to the malignant transformation of cells, but also promotes tumor progression and metastasis. As an immune-escape mechanism, the metabolic adaptation of the bone marrow microenvironment and leukemic cells is a major player in the suppression of anti-leukemia immune responses. Therefore, metabolic rewiring in leukemia would provide promising opportunities for newer therapeutic interventions. Several therapeutic agents which affect essential bioenergetic pathways in cancer cells including glycolysis, β-oxidation of fatty acids and Krebs cycle, or anabolic pathways such as lipid biosynthesis and pentose phosphate pathway, are being tested in various types of cancers. So far, numerous preclinical or clinical trial studies using such metabolic agents alone or in combination with other remedies such as immunotherapy are in progress and have demonstrated promising outcomes. In this review, we aim to argue the importance of metabolic alterations and bioenergetic pathways in different types of leukemia and their vital roles in disease development. Designing treatments based on targeting leukemic cells vulnerabilities, particularly in nonresponsive leukemia patients, should be warranted

Sestrins as a therapeutic bridge between ROS and autophagy in cancer

The regulation of Reactive Oxygen Species (ROS) levels and the contribution therein from networks regulating cell metabolism, such as autophagy and the mTOR-dependent nutrient-sensing pathway, constitute major targets for selective therapeutic intervention against several types of tumors, due to their extensive rewiring in cancer cells as compared to healthy cells. Here, we discuss the sestrin family of proteins-homeostatic transducers of oxidative stress, and drivers of antioxidant and metabolic adaptation-as emerging targets for pharmacological intervention. These adaptive regulators lie at the intersection of those two priority nodes of interest in antitumor intervention-ROS control and the regulation of cell metabolism and autophagy-therefore, they hold the potential not only for the development of completely novel compounds, but also for leveraging on synergistic strategies with current options for tumor therapy and classification/stadiation to achieve personalized medicine

The Role of TIM-3 in Hepatocellular Carcinoma: A Promising Target for Immunotherapy?

One of the most common tumors in the world is hepatocellular carcinoma (HCC), and its mortality rates are still on the rise, so addressing it is considered an important challenge for universal health. Despite the various treatments that have been developed over the past decades, the prognosis for advanced liver cancer is still poor. Recently, tumor immunotherapy has opened new opportunities for suppression of tumor progression, recurrence, and metastasis. Besides this, investigation into this malignancy due to high immune checkpoint expression and the change of immunometabolic programming in immune cells and tumor cells is highly considered. Because anti-cytotoxic T lymphocyte–associated protein (CTLA)-4 antibodies and anti-programmed cell death protein (PD)-1 antibodies have shown therapeutic effects in various cancers, studies have shown that T cell immunoglobulin mucin-3 (TIM-3), a new immune checkpoint molecule, plays an important role in the development of HCC. In this review, we summarize the recent findings on signal transduction events of TIM-3, its role as a checkpoint target for HCC therapy, and the immunometabolic situation in the progression of HCC

TIM-3/Gal-9 interaction affects glucose and lipid metabolism in acute myeloid leukemia cell lines

Introduction: T-cell immunoglobulin and mucin domain-3 (TIM-3) is a transmembrane molecule first identified as an immunoregulator. This molecule is also expressed on leukemic cells in acute myeloid leukemia and master cell survival and proliferation. In this study, we aimed to explore the effect of TIM-3 interaction with its ligand galectin-9 (Gal-9) on glucose and lipid metabolism in AML cell lines. Methods: HL-60 and THP-1 cell lines, representing M3 and M5 AML subtypes, respectively, were cultured under appropriate conditions. The expression of TIM-3 on the cell surface was ascertained by flow cytometric assay. We used real-time PCR to examine the mRNA expression of GLUT-1, HK-2, PFKFB-3, G6PD, ACC-1, ATGL, and CPT-1A; colorimetric assays to measure the concentration of glucose, lactate, GSH, and the enzymatic activity of G6PD; MTT assay to determine cellular proliferation; and gas chromatography–mass spectrometry (GC-MS) to designate FFAs. Results: We observed the significant upregulated expression of GLUT-1, HK-2, PFKFB-3, ACC-1, CPT-1A, and G6PD and the enzymatic activity of G6PD in a time-dependent manner in the presence of Gal-9 compared to the PMA and control groups in both HL-60 and THP-1 cell lines (p > 0.05). Moreover, the elevation of extracellular free fatty acids, glucose consumption, lactate release, the concentration of cellular glutathione (GSH) and cell proliferation were significantly higher in the presence of Gal-9 compared to the PMA and control groups in both cell lines (p < 0.05). Conclusion: TIM-3/Gal-9 ligation on AML cell lines results in aerobic glycolysis and altered lipid metabolism and also protects cells from oxidative stress, all in favor of leukemic cell survival and proliferation.Isfahan University of Medical Science

Interferon-alpha Up-Regulates the Expression of PD-L1 Molecules on Immune Cells Through STAT3 and p38 Signaling

Interferon-alpha (IFN alpha) has one of the longest histories of use amongst cytokines in clinical oncology and has been applied for the treatment of many types of cancers. Due to its immune-activating properties, IFN alpha is also an attractive candidate for combinatory anti-cancer therapies. Despite its extensive use in animal tumor models as well as in several clinical trials, the different mechanisms underlying patient responses and affecting desirable clinical benefits are still under investigation. Here we show that in addition to its immune-activating properties, IFN alpha induces the expression of a key negative regulator, immunosuppressive PD-L1 molecule, in the majority of the specific immune cell populations, particularly in the dendritic cells (DC). DC can modulate immune responses by a variety of mechanisms, including expression of T-cell regulatory molecules and cytokines. Our results showed that treatment of DC with IFN alpha-2b led to pronounced up-regulation of surface expression of PD-L1 molecules, increased IL-6 and decreased IL-12 production. Moreover, we present evidence that IFN alpha-treated DC exhibited a reduced capacity to stimulate interferon-gamma production in T cells compared to control DC. This T-cell response after treatment of DC with IFN alpha was recovered by a pre-treatment with an anti-PD-L1 blocking antibody. Further analyses revealed that IFN a regulated PD-L1 expression through the STAT3 and p38 signaling pathways, since blocking of STAT3 and p38 activation with specific inhibitors prevented PD-L1 up-regulation. Our findings underline the important roles of p38 and STAT3 in the regulation of PD-L1 expression and prove that IFN alpha induces STAT3/p38-mediated expression of PD-L1 and thereby a reduced stimulatory ability of DC. The augmentation of PD-L1 expression in immune cells through IFN alpha treatment should be considered by use of IFN alpha in an anti-cancer therapy

MiRNAs are Unlikely to be Involved in Retinoid Receptor Gene Regulation in Pancreatic Cancer Cells

Background/Aims: Retinoid receptors and retinoic acid were reported to be down-regulated in pancreatic duct adenocarcinoma (PDAC) compared to normal pancreas. Yet the mechanism of the down-regulation of retinoid receptors is not well defined. The aim of this study was to find out whether selected dysregulated miRNAs in PDAC are responsible for the decreased level of retinoid receptors. Methods: Bioinformatics, real-time PCR, western blot analysis as well as molecular manipulation with miRNA in cells of PDAC were carried out. Results: We first performed bioinformatics research to identify conserved target sequences for deregulated miRNAs within the 3' UTR region of retinoid receptor mRNA. This research revealed binding sites for miR-138, -27a, -27b, -206, -613, -9-5p, -27a/b-3p and -27a. Next, we investigated the expression of selected retinoid receptors and miRNAs in PDAC cell lines and in the Human Pancreatic Duct Epithelial (HPDE) cell line. Further, we investigated the effects of modifying expression levels of selected miRNAs using miRNA inhibitors or mimics. We demonstrated that none of these miRNAs can target the selected retinoid receptors in vitro. Conclusions: miR-27a, miR-27b, miR-9, miR10a and miR-10b were up-regulated in PDAC cells compared to HPDE cells. The up-regulation of these miRNAs was not responsible for the down-regulation of RARa, RAR beta, RXRa and RXR beta in PDAC cells. (C) 2017 The Author(s) Published by S. Karger AG, Base