bims-stacyt 2022-06-12 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022–06–12
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Hypoxia, a key factor in the immune microenvironment.
LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid.
Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape.
Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.
P2X Purinergic Receptors Are Multisensory Detectors for Micro-Environmental Stimuli That Control Migration of Tumoral Endothelium.
Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.
The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.

Biomed Pharmacother. 2022 Jul;pii: S0753-3322(22)00457-7. [Epub ahead of print]151 113068

Hypoxia, a key factor in the immune microenvironment.

Jingyao Hu, Xinyu Li, Liang Yang, Hangyu Li.

  The physical and chemical pressures in the tumor microenvironment (TME) play an important role in tumor development by regulating stromal elements, including immune cells. Hypoxia can induce a cascade of events in tumor initiation and development via immune regulation. As a dangerous factor, hypoxia activates multiple signaling pathways to reshape the immune microenvironment, leading to immunosuppression. Consequently, targeting hypoxia in the TME is a potential strategy to prevent immune escape and inhibit malignant tumor progression. In this review, we summarized the role of hypoxia-induced factors in the tumor immune escape process and provide a novel pathway to restrain tumor progression and development.

Keywords:  Cancer; HIF; Hypoxia; Immune escape; TME

DOI:  https://doi.org/10.1016/j.biopha.2022.113068
Int J Mol Sci. 2022 May 26. pii: 5970. [Epub ahead of print]23(11):

LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid.

Sonja-Maria Decking, Christina Bruss, Nathalie Babl, Sebastian Bittner, Sebastian Klobuch, Simone Thomas, Markus Feuerer, Petra Hoffmann, Katja Dettmer, Peter J Oefner, Kathrin Renner, Marina Kreutz.

  Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.

Keywords:  LDH; T cell metabolism; T cells; adoptive cell transfer; glycolysis; interferon gamma; lactate; lactic acid

DOI:  https://doi.org/10.3390/ijms23115970
J Hematol Oncol. 2022 Jun 03. 15(1): 77

Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape.

Qinghua Wu, Li You, Eugenie Nepovimova, Zbynek Heger, Wenda Wu, Kamil Kuca, Vojtech Adam.

  Hypoxia, a common feature of the tumor microenvironment in various types of cancers, weakens cytotoxic T cell function and causes recruitment of regulatory T cells, thereby reducing tumoral immunogenicity. Studies have demonstrated that hypoxia and hypoxia-inducible factors (HIFs) 1 and 2 alpha (HIF1A and HIF2A) are involved in tumor immune escape. Under hypoxia, activation of HIF1A induces a series of signaling events, including through programmed death receptor-1/programmed death ligand-1. Moreover, hypoxia triggers shedding of complex class I chain-associated molecules through nitric oxide signaling impairment to disrupt immune surveillance by natural killer cells. The HIF-1-galactose-3-O-sulfotransferase 1-sulfatide axis enhances tumor immune escape via increased tumor cell-platelet binding. HIF2A upregulates stem cell factor expression to recruit tumor-infiltrating mast cells and increase levels of cytokines interleukin-10 and transforming growth factor-β, resulting in an immunosuppressive tumor microenvironment. Additionally, HIF1A upregulates expression of tumor-associated long noncoding RNAs and suppresses immune cell function, enabling tumor immune escape. Overall, elucidating the underlying mechanisms by which HIFs promote evasion of tumor immune surveillance will allow for targeting HIF in tumor treatment. This review discusses the current knowledge of how hypoxia and HIFs facilitate tumor immune escape, with evidence to date implicating HIF1A as a molecular target in such immune escape. This review provides further insight into the mechanism of tumor immune escape, and strategies for tumor immunotherapy are suggested.

Keywords:  Hypoxia; Hypoxia-inducible factors; Immunotherapy; Personalized medicine; Tumor disease

DOI:  https://doi.org/10.1186/s13045-022-01292-6
Cancer Cell. 2022 May 31. pii: S1535-6108(22)00217-3. [Epub ahead of print]

Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.

Emma Kurz, Carolina Alcantara Hirsch, Tanner Dalton, Sorin Alberto Shadaloey, Alireza Khodadadi-Jamayran, George Miller, Sumedha Pareek, Hajar Rajaei, Chirayu Mohindroo, Seyda Baydogan, An Ngo-Huang, Nathan Parker, Matthew H G Katz, Maria Petzel, Emily Vucic, Florencia McAllister, Keri Schadler, Rafael Winograd, Dafna Bar-Sagi.

  Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.

Keywords:  IL-15; PD-1; T cell; checkpoint blockade; exercise; immunology; immunotherapy; pancreatic cancer; super-agonist

DOI:  https://doi.org/10.1016/j.ccell.2022.05.006
Cancers (Basel). 2022 May 31. pii: 2743. [Epub ahead of print]14(11):

P2X Purinergic Receptors Are Multisensory Detectors for Micro-Environmental Stimuli That Control Migration of Tumoral Endothelium.

Giorgia Scarpellino, Tullio Genova, Elisa Quarta, Carla Distasi, Marianna Dionisi, Alessandra Fiorio Pla, Luca Munaron.

  The tumoral microenvironment often displays peculiar features, including accumulation of extracellular ATP, hypoxia, low pH-acidosis, as well as an imbalance in zinc (Zn2+) and calcium (Ca2+). We previously reported the ability of some purinergic agonists to exert an anti-migratory activity on tumor-derived human endothelial cells (TEC) only when applied at a high concentration. They also trigger calcium signals associated with release from intracellular stores and calcium entry from the external medium. Here, we provide evidence that high concentrations of BzATP (100 µM), a potent agonist of P2X receptors, decrease migration in TEC from different tumors, but not in normal microvascular ECs (HMEC). The same agonist evokes a calcium increase in TEC from the breast and kidney, as well as in HMEC, but not in TEC from the prostate, suggesting that the intracellular pathways responsible for the P2X-induced impairment of TEC migration could vary among different tumors. The calcium signal is mainly due to a long-lasting calcium entry from outside and is strictly dependent on the presence of the receptor occupancy. Low pH, as well as high extracellular Zn2+ and Ca2+, interfere with the response, a distinctive feature typically found in some P2X purinergic receptors. This study reveals that a BzATP-sensitive pathway impairs the migration of endothelial cells from different tumors through mechanisms finely tuned by environmental factors.

Keywords:  calcium signaling; cell migration; purinergic receptors; tumor-derived endothelial cells

DOI:  https://doi.org/10.3390/cancers14112743
J Immunol. 2022 Jun 10. pii: ji2100666. [Epub ahead of print]

Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.

Cristina Mancebo, José Javier Fernández, Carmen Herrero-Sánchez, Yolanda Alvarez, Sara Alonso, Tito A Sandoval, Juan R Cubillos-Ruiz, Olimpio Montero, Nieves Fernández, Mariano Sánchez Crespo.

Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative phosphorylation (OXPHOS) to glycolysis has been considered a characteristic feature of activated immune cells. However, some stimuli might enhance both routes concomitantly. The connection between the tricarboxylic acid cycle and cytokine expression was scrutinized in human monocyte-derived dendritic cells stimulated with the fungal surrogate zymosan. Results showed that nucleocytosolic citrate and ATP-citrate lyase activity drove IL1B, IL10, and IL23A expression by yielding acetyl-CoA and oxaloacetate, with the latter one supporting glycolysis and OXPHOS by maintaining cytosolic NAD+ and mitochondrial NADH levels through mitochondrial shuttles. Succinate dehydrogenase showed a subunit-specific ability to modulate IL23A and IL10 expression. Succinate dehydrogenase A subunit activity supported cytokine expression through the control of the 2-oxoglutarate/succinate ratio, whereas C and D subunits underpinned cytokine expression by conveying electron flux from complex II to complex III of the electron transport chain. Fatty acids may also fuel the tricarboxylic acid cycle and influence cytokine expression. Overall, these results show that fungal patterns support cytokine expression through a strong boost of glycolysis and OXPHOS supported by the use of pyruvate, citrate, and succinate, along with the compartmentalized NAD(H) redox state maintained by mitochondrial shuttles.

DOI: https://doi.org/10.4049/jimmunol.2100666
PLoS Biol. 2022 Jun 10. 20(6): e3001678

The polyol pathway is an evolutionarily conserved system for sensing glucose uptake.

Hiroko Sano, Akira Nakamura, Mariko Yamane, Hitoshi Niwa, Takashi Nishimura, Kimi Araki, Kazumasa Takemoto, Kei-Ichiro Ishiguro, Hiroki Aoki, Yuzuru Kato, Masayasu Kojima.

Cells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here, we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion involves an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway regulates the glucose-responsive nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP's nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for glucose uptake that allows metabolic remodeling.

DOI: https://doi.org/10.1371/journal.pbio.3001678