bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–11–12
seven papers selected by
Oltea Sampetrean, Keio University
  1. Vitamin B6 competition in the tumor microenvironment hampers antitumor functions of NK cells.
  2. Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients.
  3. Engineering metabolism to modulate immunity.
  4. Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.
  5. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
  6. Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.
  7. Ferroptosis and tumor immunity: In perspective of the major cell components in the tumor microenvironment.
  1. Cancer Discov. 2023 Nov 07.
    Vitamin B6 competition in the tumor microenvironment hampers antitumor functions of NK cells.
    Chunbo He, Dezhen Wang, Surendra K Shukla, Tuo Hu, Ravi Thakur, Xiao Fu, Ryan J King, Sai Sundeep Kollala, Kuldeep S Attri, Divya Murthy, Nina V Chaika, Yuki Fujii, Daisy Gonzalez, Camila G Pacheco, Yudong Qiu, Pankaj K Singh, Jason W Locasale, Kamiya Mehla.
      Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect anti-tumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and anti-tumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0334
  2. Nat Commun. 2023 Nov 08. 14(1): 7211
    Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients.
    Juraj Adamik, Paul V Munson, Deena M Maurer, Felix J Hartmann, Sean C Bendall, Rafael J Argüello, Lisa H Butterfield.
      Efficacy of cancer vaccines remains low and mechanistic understanding of antigen presenting cell function in cancer may improve vaccine design and outcomes. Here, we analyze the transcriptomic and immune-metabolic profiles of Dendritic Cells (DCs) from 35 subjects enrolled in a trial of DC vaccines in late-stage melanoma (NCT01622933). Multiple platforms identify metabolism as an important biomarker of DC function and patient overall survival (OS). We demonstrate multiple immune and metabolic gene expression pathway alterations, a functional decrease in OCR/OXPHOS and increase in ECAR/glycolysis in patient vaccines. To dissect molecular mechanisms, we utilize single cell SCENITH functional profiling and show patient clinical outcomes (OS) correlate with DC metabolic profile, and that metabolism is linked to immune phenotype. With single cell metabolic regulome profiling, we show that MCT1 (monocarboxylate transporter-1), a lactate transporter, is increased in patient DCs, as is glucose uptake and lactate secretion. Importantly, pre-vaccination circulating myeloid cells in patients used as precursors for DC vaccine generation are significantly skewed metabolically as are several DC subsets. Together, we demonstrate that the metabolic profile of DC is tightly associated with the immunostimulatory potential of DC vaccines from cancer patients. We link phenotypic and functional metabolic changes to immune signatures that correspond to suppressed DC differentiation.
    DOI:  https://doi.org/10.1038/s41467-023-42881-4
  3. Adv Drug Deliv Rev. 2023 Nov 05. pii: S0169-409X(23)00437-4. [Epub ahead of print] 115122
    Engineering metabolism to modulate immunity.
    Senta M Kapnick, Corinne A Martin, Christopher M Jewell.
      Metabolic programming and reprogramming have emerged as pivotal mechanisms for altering immune cell function. Thus, immunometabolism has become an attractive target area for treatment of immune-mediated disorders. Nonetheless, many hurdles to delivering metabolic cues persist. In this review, we consider how biomaterials are poised to transform manipulation of immune cell metabolism through integrated control of metabolic configurations to affect outcomes in autoimmunity, regeneration, transplant, and cancer. We emphasize the features of nanoparticles and other biomaterials that permit delivery of metabolic cues to the intracellular compartment of immune cells, or strategies for altering signals in the extracellular space. We then provide perspectives on the potential for reciprocal regulation of immunometabolism by the physical properties of materials themselves. Lastly, opportunities for clinical translation are highlighted. This discussion contributes to our understanding of immunometabolism, biomaterials-based strategies for altering metabolic configurations in immune cells, and emerging concepts in this evolving field.
    Keywords:  biomaterials; immune engineering; immunometabolism
    DOI:  https://doi.org/10.1016/j.addr.2023.115122
  4. J Exp Clin Cancer Res. 2023 Nov 03. 42(1): 291
    Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.
    Yue Zheng, Yiran Yao, Tongxin Ge, Shengfang Ge, Renbing Jia, Xin Song, Ai Zhuang.
      Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.
    Keywords:  Amino acid; Immunotherapy; Metabolism reprogramming; T cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-023-02845-4
  5. Nat Metab. 2023 Nov 09.
    Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
    CRUK Rosetta Grand Challenge Consortium
      Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
    DOI:  https://doi.org/10.1038/s42255-023-00915-7
  6. Biochem Pharmacol. 2023 Nov 04. pii: S0006-2952(23)00500-2. [Epub ahead of print] 115907
    Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.
    Jia Lu, Siwei Chen, Xuejiao Bai, Minru Liao, Yuling Qiu, Ling-Li Zheng, Haiyang Yu.
      Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.
    Keywords:  Cancer; Cholesterol metabolism; Molecular mechanisms; Therapeutic agent; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bcp.2023.115907
  7. Eur J Pharmacol. 2023 Nov 02. pii: S0014-2999(23)00638-6. [Epub ahead of print] 176124
    Ferroptosis and tumor immunity: In perspective of the major cell components in the tumor microenvironment.
    Wanling Zhu, Xiaowei Liu, Lei Yang, Qiang He, Dingming Huang, Xuelian Tan.
      Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation, which is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. Mounting studies on the essential role of ferroptosis have been published in the progression of solid tumors, metastasis, therapy, and therapy resistance. Studies showed that ferroptosis is a "double-edged sword" in tumor immunity, which means it may have both tumor-antagonizing and tumor-promoting functions. The tumor microenvironment (TME) comprises not only tumor cells but also surrounding immune cells, stromal cells, as well as noncellular components such as the extracellular matrix (ECM), cytokines, growth factors, and extracellular vesicles (EVs). In the complex and diverse condition in TME where tumor cells grow, changes in each constituent may impact tumor destiny differently. Recently, several studies have revealed the interaction between ferroptosis and different constituents in TME. Both tumor cells and nontumor cells have a dual role in tumor immunity and influence tumor progression through ferroptosis. Herein, this review aims at summarizing the role of ferroptosis in tumor immunity based on TME, focusing on the mechanisms of the interaction between the ferroptosis and the different constituents in TME, illuminating how ferroptosis plays its role in promoting or antagonizing tumors by acting with varying components in TME and proposing several questions in immunomodulatory effects of ferroptosis and ferroptosis-associated immunotherapy.
    Keywords:  Cell death; Ferroptosis; Immune cells; Tumor immunology; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176124
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒09 at 10:21.