bims-stacyt 2021-06-27 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–06–27
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy.
Role of breast cancer-derived exosomes in metabolism of immune cells through PD1-GLUT1-HK2 metabolic axis.
The Macrophage Response Is Driven by Mesenchymal Stem Cell-Mediated Metabolic Reprogramming.
Targeting immunometabolism of neoplasms by interleukins: A promising immunotherapeutic strategy for cancer treatment.
Fever supports CD8+ effector T cell responses by promoting mitochondrial translation.
Neonatal stroke enhances interaction of microglia-derived extracellular vesicles with microglial cells.
High Glucose Activates YAP Signaling to Promote Vascular Inflammation.
Glutamine metabolism is essential for the production of IL-17A in γδ T cells and skin inflammation.

Oncogene. 2021 Jun 21.

Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy.

Audrey Lequeux, Muhammad Zaeem Noman, Malina Xiao, Kris Van Moer, Meriem Hasmim, Alice Benoit, Manon Bosseler, Elodie Viry, Tsolere Arakelian, Guy Berchem, Salem Chouaib, Bassam Janji.

Hypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

DOI: https://doi.org/10.1038/s41388-021-01846-x
Tissue Cell. 2021 Jun 15. pii: S0040-8166(21)00092-6. [Epub ahead of print]71 101576

Role of breast cancer-derived exosomes in metabolism of immune cells through PD1-GLUT1-HK2 metabolic axis.

Nazanin Joudaki, Mohammad Rashno, Ali Asadirad, Ali Khodadadi.

  Tumor cells modulate immune responses by secreting exosomes. Tumor exosomes can affect the metabolism of immune cells and increase immune inhibitory molecules such as programmed cell death protein 1 (PD-1). PD-1 inhibits the glycolysis pathway in immune cells. We investigated the role of tumor exosomes in how metabolic changes occur through the PD1-GLUT1-HK2 metabolic axisin peripheral blood mononuclear cells (PBMCs). The MDA-MB-231 cell line was cultured, serum samples from breast cancer patients were collected, and exosomes purified from serum samples and the MDA-MB-231 cell line. PBMCs were treated with purified exosomes for 72 h and, the expression of PD1-GLUT1-HK2 genes was measured by real-time PCR. Our study results showed relative expression of the HK2 gene in both groups treated with MDA-MB-231 cell line exosomes and serum exosomes of breast cancer patients was significantly increased compared to the control group (p < 0.0001). Also, the relative expression of the PD1 gene and GLUT1 gene showed a significant increase compared to the control group only in the group treated with MDA-MB-231 cell line exosomes (p < 0.0001). Therefore, Breast cancer exosomes increased the expression of key genes in the glycolysis pathway, increasing the glycolysis pathway in PBMCs. Increased expression of PD-1 could not prevent the expression of critical genes in the glycolysis pathway as in previous studies.

Keywords:  Breast cancer; Exosomes; GLUT1; Glycolysis; HK2; PD1

DOI:  https://doi.org/10.1016/j.tice.2021.101576
Front Immunol. 2021 ;12 624746

The Macrophage Response Is Driven by Mesenchymal Stem Cell-Mediated Metabolic Reprogramming.

Noymar Luque-Campos, Felipe A Bustamante-Barrientos, Carolina Pradenas, Cynthia García, María Jesús Araya, Candice Bohaud, Rafael Contreras-López, Roberto Elizondo-Vega, Farida Djouad, Patricia Luz-Crawford, Ana María Vega-Letter.

  Mesenchymal stem cells (MSCs) are multipotent adult stromal cells widely studied for their regenerative and immunomodulatory properties. They are capable of modulating macrophage plasticity depending on various microenvironmental signals. Current studies have shown that metabolic changes can also affect macrophage fate and function. Indeed, changes in the environment prompt phenotype change. Therefore, in this review, we will discuss how MSCs orchestrate macrophage's metabolic plasticity and the impact on their function. An improved understanding of the crosstalk between macrophages and MSCs will improve our knowledge of MSC's therapeutic potential in the context of inflammatory diseases, cancer, and tissue repair processes in which macrophages are pivotal.

Keywords:  autoimmunity; cancer; macrophages; mesenchymal stem cells; metabolism; tissue repair and regeneration

DOI:  https://doi.org/10.3389/fimmu.2021.624746
Cancer Lett. 2021 Jun 18. pii: S0304-3835(21)00298-6. [Epub ahead of print]518 94-101

Targeting immunometabolism of neoplasms by interleukins: A promising immunotherapeutic strategy for cancer treatment.

Ziwen Zhu, Pooja Parikh, Hongyun Zhao, Nathan T Givens, Damien B Beck, Conner M Willson, Qian Bai, Mark R Wakefield, Yujiang Fang.

  In recent years, tumor metabolism has become a prevalent research topic for scientists and pharmaceutical companies. As research in the field has progressed, the metabolism-based therapy of tumors has ushered in new opportunities. Most tumors emerge and evolve under selective pressure from their microenvironment, which promotes the diversification of both neoplastic and non-neoplastic compartments of the tumor microenvironment (TME), and finally reaches a certain degree of intratumoral heterogeneity. As a result of the tumor intratumoral heterogeneity, tumor cells often possess a complex energy metabolism phenotype. During tumor progression, the metabolism for both tumor parenchyma and stroma is reprogrammed. The tumor stroma mainly consists of the extracellular matrix, fibroblasts, and immune cells. Interestingly, tumor-infiltrating immune cells utilize different metabolites based on their subtype and function, and these immunometabolic pathways can be modified in the TME. In particular, interleukins play a vital role in the activation and differentiation of immune cells and have exhibited multiple effects on tumor cell neoplasia, invasion, and metastasis. In this review, we summarize the common mechanisms of interleukins affecting the tumor and tumor-infiltrating immune cells metabolically and discuss how these mechanisms may lead to novel therapeutic opportunities. This review might contribute to the novel development of cancer immunotherapy.

Keywords:  Cytokine; Immunometabolism; Immunotherapy; Interleukins; Tumor metabolism

DOI:  https://doi.org/10.1016/j.canlet.2021.06.013
Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2023752118. [Epub ahead of print]118(25):

Fever supports CD8+ effector T cell responses by promoting mitochondrial translation.

David O'Sullivan, Michal A Stanczak, Matteo Villa, Franziska M Uhl, Mauro Corrado, Ramon I Klein Geltink, David E Sanin, Petya Apostolova, Nisha Rana, Joy Edwards-Hicks, Katarzyna M Grzes, Agnieszka M Kabat, Ryan L Kyle, Mario Fabri, Jonathan D Curtis, Michael D Buck, Annette E Patterson, Annamaria Regina, Cameron S Field, Francesc Baixauli, Daniel J Puleston, Edward J Pearce, Robert Zeiser, Erika L Pearce.

  Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.

Keywords:  T cell; fever; immunology; metabolism; mitochondria

DOI:  https://doi.org/10.1073/pnas.2023752118
Neurobiol Dis. 2021 Jun 18. pii: S0969-9961(21)00180-7. [Epub ahead of print] 105431

Neonatal stroke enhances interaction of microglia-derived extracellular vesicles with microglial cells.

Matthieu Lecuyer, Praneeti Pathipati, Joel Faustino, Zinaida S Vexler.

  Microglial cells support brain homeostasis under physiological conditions and modulate brain injury in a context-dependent and brain maturation-dependent manner. Microglial cells protect neonatal brain from acute stroke. While microglial signaling via direct cell-cell interaction and release of variety of molecules is intensely studied, less is known about microglial signaling via release and uptake of extracellular vesicles (EVs). We asked whether neonatal stroke alters release of microglial EVs (MEV) and MEV communication with activated microglia. We pulled down and plated microglia from ischemic-reperfused and contralateral cortex 24 h after transient middle cerebral artery occlusion (tMCAO) in postnatal day 9 mice, isolated and characterized microglia-derived microvesicles (P3-MEV) and exosomes (P4-MEV), and determined uptake of fluorescently labeled P3-MEV and P4-MEV by plated microglia derived from ischemic-reperfused and contralateral cortex. We then examined how reducing EVs release in neonatal brain-by intra-cortical injection of CRISPR-Cas9-Smpd3/KO (Smpd3/KD) to downregulate Smpd3 gene to disrupt neutral sphingomyelinase-2 (N-SMase2)-impacts P3-MEV and P4-MEV release and stroke injury. Both size and protein composition differed between P3-MEV and P4-MEV. tMCAO further altered protein composition of P3-MEV and P4-MEV and significantly, up to 5-fold, increased uptake of both vesicle subtypes by microglia from ischemic-reperfused regions. Under physiological conditions neurons were the predominant cell type expressing N-SMase-2, an enzyme involved in lipid signaling and EVs release. After tMCAO N-SMase-2 expression was diminished in injured neurons but increased in activated microglia/macrophages, leading to overall reduced N-SMase-2 activity. Compared to intracerebral injection of control plasmid, CRISPR-Cas9-Smpd3/Ct, Smpd3/KD injection further reduced N-SMase-2 activity and significantly reduced injury. Smpd3 downregulation decreased MEV release from injured regions, reduced Smpd3/KD-P3-MEV uptake and abolished Smpd3/KD-P4-MEV uptake by microglia from ischemic-reperfused region. Cumulatively, these data demonstrate that microglial cells release both microvesicles and exosomes in naïve neonatal brain, that the state of microglial activation determines both properties of released EVs and their recognition/uptake by microglia in ischemic-reperfused and control regions, suggesting a modulatory role of MEV in neonatal stroke, and that sphingosine/N-SMase-2 signaling contributes both to EVs release and uptake (predominantly P4-MEV) after neonatal stroke.

Keywords:  Exosomes; Microvesicles; Middle cerebral artery occlusion; Neonate; Perinatal stroke; Sphingosine phosphate

DOI:  https://doi.org/10.1016/j.nbd.2021.105431
Front Physiol. 2021 ;12 665994

High Glucose Activates YAP Signaling to Promote Vascular Inflammation.

Jeremy Ortillon, Jean-Christophe Le Bail, Elise Villard, Bertrand Léger, Bruno Poirier, Christine Girardot, Sandra Beeske, Laetitia Ledein, Véronique Blanchard, Patrice Brieu, Souâd Naimi, Philip Janiak, Etienne Guillot, Marco Meloni.

   Background and Aims: The YAP/TAZ signaling is known to regulate endothelial activation and vascular inflammation in response to shear stress. Moreover, YAP/TAZ signaling plays a role in the progression of cancers and renal damage associated with diabetes. However, whether YAP/TAZ signaling is also implicated in diabetes-associated vascular complications is not known.
Methods: The effect of high glucose on YAP/TAZ signaling was firstly evaluated in vitro on endothelial cells cultured under static conditions or subjected to shear stress (either laminar or oscillatory flow). The impact of diabetes on YAP/TAZ signaling was additionally assessed in vivo in db/db mice.
Results: In vitro, we found that YAP was dephosphorylated/activated by high glucose in endothelial cells, thus leading to increased endothelial inflammation and monocyte attachment. Moreover, YAP was further activated when high glucose was combined to laminar flow conditions. YAP was also activated by oscillatory flow conditions but, in contrast, high glucose did not exert any additional effect. Interestingly, inhibition of YAP reduced endothelial inflammation and monocyte attachment. Finally, we found that YAP is also activated in the vascular wall of diabetic mice, where inflammatory markers are also increased.
Conclusion: With the current study we demonstrated that YAP signaling is activated by high glucose in endothelial cells in vitro and in the vasculature of diabetic mice, and we pinpointed YAP as a regulator of high glucose-mediated endothelial inflammation and monocyte attachment. YAP inhibition may represent a potential therapeutic opportunity to improve diabetes-associated vascular complications.

Keywords:  YAP/TAZ; diabetes; endothelial cells; inflammation; vascular complications

DOI:  https://doi.org/10.3389/fphys.2021.665994
Tissue Cell. 2021 Jun 04. pii: S0040-8166(21)00085-9. [Epub ahead of print]71 101569

Glutamine metabolism is essential for the production of IL-17A in γδ T cells and skin inflammation.

Guanhua Li, Lu Liu, Zhihua Yin, Zhizhong Ye, Nan Shen.

  γδ T cell is one of the most important pathogenic immune cells in autoimmunity, especially in mucosal and epithelial diseases. Metabolism is essential for the maintenance of immune homeostasis. However, unlike αβ T cells, the metabolic regulation of γδ T cell activation still remain unclear. Here, we identified glutamine metabolism as a critical regulator for the generation of IL-17-producing γδ T cells. Metabolic screening uncovered that amino acids related to glutamine metabolism increased most obviously during γδ T cell activation. Pharmaceutical blocking of glutamine impaired IL-17 production in γδ T cells both in vitro and in vivo. Mechanism studies further revealed that genes downregulated upon glutamine deprivation enriched in IL-17 and IL-23/STAT3 signaling pathways. Consistent with this, the activation of STAT3 was suppressed after glutamine blocking. More importantly, application of glutamine antagonist in vivo alleviated the progression of IL-23 induced psoriatic mice model. In addition, both the glutamine level and the expression of glutamine related enzymes were found higher in psoriasis patients when compared with healthy controls. Therefore, our work identified an important metabolic regulatory pathway in γδ T cell activation and suggested that glutamine metabolism could be used as a target for the treatment of γδ T cell related diseases.

Keywords:  Autoimmune disease; Glutamine metabolism; γδ T cell

DOI:  https://doi.org/10.1016/j.tice.2021.101569