Solute carriers of the glucose transporter (GLUT) family mediate the first step for cellular glucose usage. The upregulation of GLUTs has been reported in numerous cancer types as a result of ...perturbation of gene expression or protein relocalization or stabilization. Because they enable to sustain the energy demand required by tumor cells for various biochemical programs, they are promising targets for the development of anticancer strategies. Recently, important biological insights have come from the fine crystal structure determination of several GLUTs; these advances will likely catalyze the development of new selective inhibitory compounds. Furthermore, deregulated glucose metabolism of nontumor cells in the tumor mass is beginning to be appreciated and could have major implications for our understanding of how glucose uptake by specific cell types influences the behavior of neighboring cells in the same microenvironment. In this review, we discuss some of the deregulation mechanisms of glucose transporters, their genetic and pharmacological targeting in cancer, and new functions they may have in nontumor cells of the tumor environment or beyond glucose uptake for glycolysis.
This review summarizes our current knowledge on glucose transporter regulation and function in cancer. It highlights recent investigations on their fine structure determination, which could be critical for the development of inhibitory compounds. It also considers the complexity of the tumor microenvironment, where glucose transporters might contribute to cancer development beyond acting solely in tumor cells.
Abstract
Neutrophils are an essential part of the innate immune system. To study their importance, experimental studies often aim to deplete these cells, generally by injecting anti-Ly6G or anti-Gr1 ...antibodies. However, these approaches are only partially effective, transient or lack specificity. Here we report that neutrophils remaining after anti-Ly6G treatment are newly derived from the bone marrow, instead of depletion escapees. Mechanistically, newly generated, circulating neutrophils have lower Ly6G membrane expression, and consequently reduced targets for anti-Ly6G-mediated depletion. To overcome this limitation, we develop a double antibody-based depletion strategy that enhances neutrophil elimination by anti-Ly6G treatment. This approach achieves specific, durable and controlled reduction of neutrophils in vivo, and may be suitable for studying neutrophil function in experimental models.
The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and eliminate them. Indeed, Toll-like receptors are a class of membrane receptors that sense ...extracellular microbes and trigger anti-pathogen signalling cascades. Recently, intracellular microbial sensors have also been identified, including NOD-like receptors and the helicase-domain-containing antiviral proteins RIG-I and MDA5. Some of these cytoplasmic molecules sense microbial, as well as non-microbial, danger signals, but the mechanisms of recognition used by these sensors remain poorly understood. Nonetheless, it is apparent that these proteins are likely to have critical roles in health and disease.
Depleting regulatory T cells (T
cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to ...systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T
cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T
cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T
cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T
cells suppressed tumor growth accompanied by a decrease in intratumoral T
cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T
cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
The early detection by the host of invading microorganisms, including viruses, depends on a limited number of specific receptors that recognize pathogen-associated molecular patterns (PAMPs). A few ...of these PAMPs, including ssRNA and dsRNA, are recognized by Toll-like receptors (TLR)-7/8 and TLR3, respectively. Activation of an antiviral TLR-dependent signaling cascade leads to the activation of the key transcription factors IRF and NF-κB, which promote antiviral responses through induction of specific genes. Recently, a second system has been described, which relies on the cytoplasmic recognition of dsRNA by RNA helicases such as RIG-I. In this review, we discuss the mechanistic aspects of these important arms of the host innate response to dsRNA and a few viral strategies utilized to counteract them.
The immune checkpoint blockade-based immunotherapies are revolutionizing cancer management. Tumor-associated neutrophils (TANs) were recently highlighted to have a pivotal role in modulating the ...tumor microenvironment and the antitumor immune response. However, these cells were largely ignored during the development of therapies based on programmed cell death receptor or ligand-1 and cytotoxic T lymphocyte antigen-4 immune checkpoint inhibitors (ICIs). Latest evidences of neutrophil functional diversity in tumor raised many questions and suggest that targeting these cells can offer new treatment opportunities in the context of ICI development. Here, we summarized key information on TAN origin, function, and plasticity that should be considered when developing ICIs and provide a detailed review of the ongoing clinical trials that combine ICIs and a second compound that might affect or be affected by TANs. This review article synthetizes important notions from the literature demonstrating that: (1) Cancer development associates with a profound alteration of neutrophil biogenesis and function that can predict and interfere with the response to ICIs, (2) Neutrophil infiltration in tumor is associated with key features of resistance to ICIs, and (3) TANs play an important role in resistance to antiangiogenic drugs reducing their clinical benefit when used in combination with ICIs. Finally, exploring the clinical/translational aspects of neutrophil impact on the response to ICIs offers the opportunity to propose new translational research avenues to better understand TAN biology and treat patients.
Since the discovery of the first member ten years ago, the receptor-interacting protein (RIP) family kinases have emerged as essential sensors of cellular stress. The different members integrate both ...extracellular stress signals transmitted by various cell-surface receptors and signals emanating from intracellular stress. The cascades of events initiated by activated RIPs are complex. Not only are pro-survival, inflammatory and immune responses triggered by RIP kinases via the activation of transcription factors such as NF-κB and AP-1, but opposing, death-inducing programs can also be initiated by the RIP kinases. Hence, RIP kinases are crucial regulators of cell survival and cell death.
Understanding the immune compartment of tumors facilitates the development of revolutionary new therapies. We used a Kras(G12D)-driven mouse model of lung cancer to establish an immune signature and ...identified a contribution of Gr1+ neutrophils to disease progression. Depletion experiments showed that Gr1+ cells (1) favor tumor growth, (2) reduce T cell homing and prevent successful anti-PD1 immunotherapy, and (3) alter angiogenesis, leading to hypoxia and sustained Snail expression in lung cancer cells. In turn, Snail accelerated disease progression and increased intratumoral Cxcl2 secretion and neutrophil infiltration. Cxcl2 was produced mainly by neutrophils themselves in response to a factor secreted by Snail-expressing tumor cells. We therefore propose a vicious cycle encompassing neutrophils and Snail to maintain a deleterious tumor microenvironment.
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•An unsupervised immune signature allows stratification of poorly immunogenic tumors•Neutrophil depletion reverts immune exclusion allowing anti-PD1 treatment efficacy•Neutrophils alter angiogenesis, increasing hypoxia and stabilizing Snail•Snail favors neutrophil homing, induces partial EMT, and enhances tumor progression
Faget et al. extract an immune signature from lung tumors pointing to neutrophils as contributors to disease progression. They show that neutrophils inhibit immunotherapy efficacy and alter angiogenesis, increasing tumor hypoxia and Snail expression. Snail enhances tumor growth and neutrophil recruitment, establishing an amplification loop favoring cancer aggressiveness.
Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double-stranded (ds) RNA, is a replication product of ...most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-κB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKα, IKKβ and IKK kinases by means of its C-terminal region, leading to the activation of NF-κB and IRF3. Overexpression of Cardif results in interferon-β and NF-κB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-β production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.
Activation of caspase-1 and subsequent processing and secretion of the pro-inflammatory cytokine IL-1β is triggered upon assembly of the inflammasome complex 1. It is generally believed that ...bacterial lipopolysaccharides (LPS) are activators of the inflammasome through stimulation of Toll-like receptor 4 (TLR4) 2. Like TLRs, NALP3/Cryopyrin, which is a key component of the inflammasome 3, contains Leucine-Rich-Repeats (LRRs). LRRs are frequently used to sense bacterial components 1, 4, 5, thus raising the possibility that bacteria directly activate the inflammasome. Here, we show that bacterial peptidoglycans (PGN), but surprisingly not LPS, induce NALP3-mediated activation of caspase-1 and maturation of proIL-1β. Activation is independent of TLRs because the PGN degradation product muramyl dipeptide (MDP), which is not sensed by TLRs, is the minimal-activating structure. Macrophages from a patient with Muckle-Wells syndrome, an autoinflammatory disease associated with mutations in the NALP3/Cryopyrin gene, show increased IL-1β secretion in the presence of MDP. The activation of the NALP3-inflammasome by MDP may be the basis of the potent adjuvant activity of MDP.
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