bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2024–01–28
nine papers selected by
Alex Muir, University of Chicago
  1. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
  2. Metabolic heterogeneity in cancer.
  3. Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties.
  4. Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.
  5. The Tumor Microenvironment and Immune Response in Breast Cancer.
  6. Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
  7. The impact of broad glutamine metabolism inhibition on the tumor microenvironment.
  8. Lipid peroxidation of immune cells in cancer.
  9. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
  1. Cancer Discov. 2024 Jan 25. OF1-OF22
    EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
    Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Ramya S Kuna, Kacie A Traina, Camila Robles-Oteíza, Deborah Ayeni, Elizabeth M Kwong, Stellar Levy, Anna-Maria Globig, Matthew M Nobari, George Z Cheng, Sandra L Leibel, Robert J Homer, Reuben J Shaw, Christian M Metallo, Katerina Politi, Susan M Kaech.
      The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
    SIGNIFICANCE: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0434
  2. Nat Metab. 2024 Jan 24.
    Metabolic heterogeneity in cancer.
    Margherita Demicco, Xiao-Zheng Liu, Katharina Leithner, Sarah-Maria Fendt.
      Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumour metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterisation of metabolic heterogeneity in tumours. In addition to the metabolic heterogeneity observed in primary tumours, metabolic heterogeneity temporally evolves along with tumour progression. In this Review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment.
    DOI:  https://doi.org/10.1038/s42255-023-00963-z
  3. bioRxiv. 2024 Jan 08. pii: 2024.01.05.574065. [Epub ahead of print]
    Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties.
    Edward R Neves, Achal Anand, Joseph Mueller, Roddel A Remy, Hui Xu, Kim A Selting, Jann N Sarkaria, Brendan Ac Harley, Sara Pedron-Haba.
      Despite extensive advances in cancer research, glioblastoma (GBM) still remains a very locally invasive and thus challenging tumor to treat, with a poor median survival. Tumor cells remodel their microenvironment and utilize extracellular matrix to promote invasion and therapeutic resistance. We aim here to determine how GBM cells exploit hyaluronan (HA) to maintain proliferation using ligand-receptor dependent and ligand-receptor independent signaling. We use tissue engineering approaches to recreate the three-dimensional tumor microenvironment in vitro, then analyze shifts in metabolism, hyaluronan secretion, HA molecular weight distribution, as well as hyaluronan synthetic enzymes (HAS) and hyaluronidases (HYAL) activity in an array of patient derived xenograft GBM cells. We reveal that endogenous HA plays a role in mitochondrial respiration and cell proliferation in a tumor subtype dependent manner. We propose a tumor specific combination treatment of HYAL and HAS inhibitors to disrupt the HA stabilizing role in GBM cells. Taken together, these data shed light on the dual metabolic and ligand - dependent signaling roles of hyaluronan in glioblastoma.
    Significance: The control of aberrant hyaluronan metabolism in the tumor microenvironment can improve the efficacy of current treatments. Bioengineered preclinical models demonstrate potential to predict, stratify and accelerate the development of cancer treatments.
    DOI:  https://doi.org/10.1101/2024.01.05.574065
  4. Front Immunol. 2023 ;14 1307228
    Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.
    Yanru Long, Houhui Shi, Yuedong He, Xiaorong Qi.
      Tumor metabolism and tumor immunity are inextricably linked. Targeting the metabolism of tumors is a point worth studying in tumor immunotherapy. Recently, the influence of the metabolism of tumors and immune cells on the occurrence, proliferation, metastasis, and prognosis of tumors has attracted more attention. Tumor tissue forms a specific tumor microenvironment (TME). In addition to tumor cells, there are also immune cells, stromal cells, and other cells in TME. To adapt to the environment, tumor cells go through the metabolism reprogramming of various substances. The metabolism reprogramming of tumor cells may further affect the formation of the tumor microenvironment and the function of a variety of cells, especially immune cells, eventually promoting tumor development. Therefore, it is necessary to study the metabolism of tumor cells and its effects on immune cells to guide tumor immunotherapy. Inhibiting tumor metabolism may restore immune balance and promote the immune response in tumors. This article will describe glucose metabolism, lipid metabolism, amino acid metabolism, and immune cells in tumors. Besides, the impact of metabolism on the immune cells in TME is also discussed for analyzing and exploring tumor immunotherapy.
    Keywords:  amino acid metabolism; glucose metabolism; immunotherapy; lipid metabolism; metabolism reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1307228
  5. Int J Mol Sci. 2024 Jan 11. pii: 914. [Epub ahead of print]25(2):
    The Tumor Microenvironment and Immune Response in Breast Cancer.
    Behjatolah Monzavi-Karbassi, Thomas Kelly, Steven R Post.
      The complex interactions between cancer cells and their surrounding microenvironment are fundamental in determining tumor progression, response to therapy, and, ultimately, patient prognosis [...].
    DOI:  https://doi.org/10.3390/ijms25020914
  6. Cell Death Discov. 2024 Jan 20. 10(1): 39
    Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
    Sheng Zhang, Kebing Lv, Zhen Liu, Ran Zhao, Fei Li.
      Metabolic competition between tumour cells and immune cells for limited nutrients is an important feature of the tumour microenvironment (TME) and is closely related to the outcome of tumour immune escape. A large number of studies have proven that tumour cells need metabolic reprogramming to cope with acidification and hypoxia in the TME while increasing energy uptake to support their survival. Among them, synthesis, oxidation and uptake of fatty acids (FAs) in the TME are important manifestations of lipid metabolic adaptation. Although different immune cell subsets often show different metabolic characteristics, various immune cell functions are closely related to fatty acids, including providing energy, providing synthetic materials and transmitting signals. In the face of the current situation of poor therapeutic effects of tumour immunotherapy, combined application of targeted immune cell fatty acid metabolism seems to have good therapeutic potential, which is blocked at immune checkpoints. Combined application of adoptive cell therapy and cancer vaccines is reflected. Therefore, it is of great interest to explore the role of fatty acid metabolism in immune cells to discover new strategies for tumour immunotherapy and improve anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s41420-024-01807-9
  7. Genes Dis. 2024 May;11(3): 100984
    The impact of broad glutamine metabolism inhibition on the tumor microenvironment.
    Tianhe Li, Yun-Ta Chuang, Tian-Li Wang.
      
    DOI:  https://doi.org/10.1016/j.gendis.2023.05.003
  8. Front Immunol. 2023 ;14 1322746
    Lipid peroxidation of immune cells in cancer.
    Liuling Xiao, Miao Xian, Chuanchao Zhang, Qi Guo, Qing Yi.
      Growing evidence indicates that cellular metabolism is a critical determinant of immune cell viability and function in antitumor immunity and lipid metabolism is important for immune cell activation and adaptation to the tumor microenvironment (TME). Lipid peroxidation is a process in which oxidants attack lipid-containing carbon-carbon double bonds and is an important part of lipid metabolism. In the past decades, studies have shown that lipid peroxidation participates in signal transduction to control cell proliferation, differentiation, and cell death, which is essential for cell function execution and human health. More importantly, recent studies have shown that lipid peroxidation affects immune cell function to modulate tumor immunity and antitumor ability. In this review, we briefly overview the effect of lipid peroxidation on the adaptive and innate immune cell activation and function in TME and discuss the effectiveness and sensitivity of the antitumor ability of immune cells by regulating lipid peroxidation.
    Keywords:  TME; adaptive immune cells; innate immune cells; lipid peroxidation; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1322746
  9. Nat Immunol. 2024 Jan 23.
    Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
    Jingwei Ma, Liang Tang, Yaoyao Tan, Jingxuan Xiao, Keke Wei, Xin Zhang, Yuan Ma, Shuai Tong, Jie Chen, Nannan Zhou, Li Yang, Zhang Lei, Yonggang Li, Jiadi Lv, Junwei Liu, Huafeng Zhang, Ke Tang, Yi Zhang, Bo Huang.
      The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-023-01738-0
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