Lactate generated from pyruvate fuels production of intracellular NAD(+) as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the ...metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IκBα, and then stimulate an autocrine NF-κB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8-targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8-dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-κB/IL-8 pathway as an important link between tumor metabolism and angiogenesis.
Splicing is a phenomenon enabling the excision of introns from pre-mRNA to give rise to mature mRNA. All the 20,000 genes of the human genome are concerned by this mechanism. Nevertheless, it is ...estimated that the proteome is composed of more than 100,000 proteins. How to go from 20,000 genes to more than 100,000 proteins? Alternative splicing (AS) is in charge of this diversity of proteins. AS which is found in most of the cells of an organism, participates in normal cells and in particular in immune cells, in the regulation of cellular behavior. In cancer, AS is highly dysregulated and involved in almost all of the hallmarks that characterize tumor cells. In view of the close link that exists between tumors and the immune system, we present in this review the literature relating to alternative splicing and immunotherapy. We also provide a global but not exhaustive view of AS in the immune system and tumor cells linked to the events that can lead to AS dysregulation in tumors.
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological ...function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.
Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the ...differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence suggests that modified energy metabolism could be responsible for the failure of antitumor immunity. Indeed, tumor-infiltrating immune cells play a key role in cancer, and metabolic switching in these cells has been shown to help determine their phenotype: tumor suppressive or immune suppressive. Recent studies in the field of immunometabolism focus on metabolic reprogramming in the tumor microenvironment (TME) by targeting innate and adaptive immune cells and their associated anti- or protumor phenotypes. In this review, we discuss the lipid metabolism of immune cells in the TME as well as the effects of lipids; finally, we expose the link between therapies and lipid metabolism.
Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the ...cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4+ and CD8+ T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
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► Th17 cells express CD39 and CD73 ectonucleotidases ► Ectonucleotidase expression is transcriptionally regulated by STAT3 and GFI-1 ► Ectonucleotidase expression determines inflammatory vs suppressive fate of Th17 cells
The advancement of knowledge on tumor biology over the past decades has demonstrated a close link between tumor cells and cells of the immune system. In this context, cytokines have a major role ...because they act as intermediaries in the communication into the tumor bed. Cytokines play an important role in the homeostasis of innate and adaptive immunity. In particular, they participate in the differentiation of CD4 T lymphocytes. These cells play essential functions in the anti-tumor immune response but can also be corrupted by tumors. The differentiation of naïve CD4 T cells depends on the cytokine environment in which they are activated. Additionally, at the tumor site, their activity can also be modulated according to the cytokines of the tumor microenvironment. Thus, polarized CD4 T lymphocytes can see their phenotype evolve, demonstrating functional plasticity. Knowledge of the impact of these cytokines on the functions of CD4 T cells is currently a source of innovation, for therapeutic purposes. In this review, we discuss the impact of the major cytokines present in tumors on CD4 T cells. In addition, we summarize the main therapeutic strategies that can modulate the CD4 response through their impact on cytokine production.
Survivin, a small member of the inhibitors of the apoptosis protein family, is highly deregulated in cancer. It is weakly expressed in normal tissues but very strongly expressed in malignant lesions. ...Survivin is involved in cell-cycle progression, especially in the G2/M transition, and has anti-apoptotic activity, which correlates with its strong expression in cases with a poor cancer treatment response and poor outcomes. Several therapies that target the survivin transcript or protein are currently being tested in clinical trials. However, focusing new therapies on the origins of survivin overexpression and targeting these upstream deregulations could be more effective. For this reason, it seems important to make an inventory of the transcriptional (de)regulation of survivin. This review will gather the important points concerning the regulation of survivin mRNA expression: structure of the
survivin
promoter, epigenetic modifications and genetic abnormalities, transcription factors, and signalling pathways that affect survivin mRNA expression.
CD4 T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans. The biology of CD4 T cells is complex because naïve T cells can ...differentiate into various subpopulations with various functions. Recently, a new population called Th9 cells was described. These cells are characterized by their ability to produce IL9 and IL21. They were first described in the context of parasite infections and allergic processes. However, some reports described their presence in the tumor bed in mice and humans. Their high secretion of IL9 and IL21 in the tumor bed contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response, thus explaining the remarkable ability of Th9 cells to control tumor growth. This review summarizes the latest advances in the Th9 field in cancer and focuses on their potential role as new tool for cell therapy.
IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and ...cancer progression have been recently revisited following the discovery of T
H
9 cells. T
H
9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, T
H
9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human T
H
9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of T
H
9 cells and their possible clinical relevance for cancer immunotherapy.
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