bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–01–28
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
  2. Role of Tumor Cell Intrinsic and Host Autophagy in Cancer.
  3. Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.
  4. Glioma-Immune Cell Crosstalk in Tumor Progression.
  5. Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
  6. Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy.
  7. CD36: The Bridge between Lipids and Tumors.
  8. Nano-medicine therapy reprogramming metabolic network of tumor microenvironment: new opportunity for cancer therapies.
  9. The impact of broad glutamine metabolism inhibition on the tumor microenvironment.
  10. Editorial: The tumor and microenvironment crosstalk in breast cancer: from biology to therapeutic opportunity.
  11. Metabolic heterogeneity in cancer.
  12. New sights of immunometabolism and agent progress in colitis associated colorectal cancer.
  13. Lipid peroxidation of immune cells in cancer.
  14. 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. Cold Spring Harb Perspect Med. 2024 Jan 22. pii: a041539. [Epub ahead of print]
    Role of Tumor Cell Intrinsic and Host Autophagy in Cancer.
    Jessie Yanxiang Guo, Eileen White.
      Macroautophagy (autophagy hereafter) is an intracellular nutrient scavenging pathway induced by starvation and other stressors whereby cellular components such as organelles are captured in double-membrane vesicles (autophagosomes), whereupon their contents are degraded through fusion with lysosomes. Two main purposes of autophagy are to recycle the intracellular breakdown products to sustain metabolism and survival during starvation and to eliminate damaged or excess cellular components to suppress inflammation and maintain homeostasis. In contrast to most normal cells and tissues in the fed state, tumor cells up-regulate autophagy to promote their growth, survival, and malignancy. This tumor-cell-autonomous autophagy supports elevated metabolic demand and suppresses tumoricidal activation of the innate and adaptive immune responses. Tumor-cell-nonautonomous (e.g., host) autophagy also supports tumor growth by maintaining essential tumor nutrients in the circulation and tumor microenvironment and by suppressing an antitumor immune response. In the setting of cancer therapy, autophagy is a resistance mechanism to chemotherapy, targeted therapy, and immunotherapy. Thus, tumor and host autophagy are protumorigenic and autophagy inhibition is being examined as a novel therapeutic approach to treat cancer.
    DOI:  https://doi.org/10.1101/cshperspect.a041539
  3. 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
  4. Cancers (Basel). 2024 Jan 11. pii: 308. [Epub ahead of print]16(2):
    Glioma-Immune Cell Crosstalk in Tumor Progression.
    Mahmoud Elguindy, Jacob S Young, Isha Mondal, Rongze O Lu, Winson S Ho.
      Glioma progression is a complex process controlled by molecular factors that coordinate the crosstalk between tumor cells and components of the tumor microenvironment (TME). Among these, immune cells play a critical role in cancer survival and progression. The complex interplay between cancer cells and the immune TME influences the outcome of immunotherapy and other anti-cancer therapies. Here, we present an updated view of the pro- and anti-tumor activities of the main myeloid and lymphocyte cell populations in the glioma TME. We review the underlying mechanisms involved in crosstalk between cancer cells and immune cells that enable gliomas to evade the immune system and co-opt these cells for tumor growth. Lastly, we discuss the current and experimental therapeutic options being developed to revert the immunosuppressive activity of the glioma TME. Knowledge of the complex interplay that elapses between tumor and immune cells may help develop new combination treatments able to overcome tumor immune evasion mechanisms and enhance response to immunotherapies.
    Keywords:  glioma; immune; immune evasion; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16020308
  5. 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
  6. Curr Cancer Drug Targets. 2024 Jan 24.
    Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy.
    Zongrui Xing, Xiangyan Jiang, Yuxia Wu, Zeyuan Yu.
      Tumors of the digestive system are currently one of the leading causes of cancer-related death worldwide. Despite considerable progress in tumor immunotherapy, the prognosis for most patients remains poor. In the tumor microenvironment (TME), tumor cells attain immune escape through immune editing and acquire immune tolerance. The mevalonate pathway and autophagy play important roles in cancer biology, antitumor immunity, and regulation of the TME. In addition, there is metabolic crosstalk between the two pathways. However, their role in promoting immune tolerance in digestive system tumors has not previously been summarized. Therefore, this review focuses on the cancer biology of the mevalonate pathway and autophagy, the regulation of the TME, metabolic crosstalk between the pathways, and the evaluation of their efficacy as targeted inhibitors in clinical tumor immunotherapy.
    Keywords:  Mevalonate pathway; antitumor immunotherapy; autophagy; metabolic crosstalk; tumor microenvironment.
    DOI:  https://doi.org/10.2174/0115680096273730231206054104
  7. Molecules. 2024 Jan 21. pii: 531. [Epub ahead of print]29(2):
    CD36: The Bridge between Lipids and Tumors.
    Xuan Zhou, Manman Su, Jungu Lu, Deming Li, Xinhui Niu, Yi Wang.
      It has been found that the development of some cancers can be attributed to obesity, which is associated with the excessive intake of lipids. Cancer cells undergo metabolic reprogramming, shifting from utilizing glucose to fatty acids (FAs) for energy. CD36, a lipid transporter, is highly expressed in certain kinds of cancer cells. High expressions of CD36 in tumor cells triggers FA uptake and lipid accumulation, promoting rapid tumor growth and initiating metastasis. Meanwhile, immune cells in the tumor microenvironment overexpress CD36 and undergo metabolic reprogramming. CD36-mediated FA uptake leads to lipid accumulation and has immunosuppressive effects. This paper reviews the types of FAs associated with cancer, high expressions of CD36 that promote cancer development and progression, effects of CD36 on different immune cells in the tumor microenvironment, and the current status of CD36 as a therapeutic target for the treatment of tumors with high CD36 expression.
    Keywords:  CD36; fatty acid; immunosuppress; lipid; metastasis-initiating cells
    DOI:  https://doi.org/10.3390/molecules29020531
  8. J Drug Target. 2024 Jan 22. 1-47
    Nano-medicine therapy reprogramming metabolic network of tumor microenvironment: new opportunity for cancer therapies.
    Xiaojie Zhang, Min An, Juntao Zhang, Yumeng Zhao, Yanhua Liu.
      Metabolic heterogeneity is one of the characteristics of tumor cells. In order to adapt to the tumor microenvironment of hypoxia, acidity and nutritional deficiency, tumor cells have undergone extensive metabolic reprogramming. Metabolites involved in tumor cell metabolism are also very different from normal cells, such as a large number of lactate and adenosine. Metabolites play an important role in regulating the whole tumor microenvironment. Taking metabolites as the target, it aims to change the metabolic pattern of tumor cells again, destroy the energy balance it maintains, activate the immune system, and finally kill tumor cells. In this paper, the regulatory effects of metabolites such as lactate, glutamine, arginine, tryptophan, fatty acids and adenosine were reviewed, and the related targeting strategies of nano-medicines were summarized, and the future therapeutic strategies of nano-drugs were discussed. The abnormality of tumor metabolites caused by tumor metabolic remodeling not only changes the energy and material supply of tumor, but also participates in the regulation of tumor-related signal pathways, which plays an important role in the survival, proliferation, invasion and metastasis of tumor cells. Regulating the availability of local metabolites is a new aspect that affects tumor progress.
    Keywords:  immune cells; metabolite; nano-medicine; tumor microenvironment
    DOI:  https://doi.org/10.1080/1061186X.2024.2309565
  9. 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
  10. Front Oncol. 2023 ;13 1339294
    Editorial: The tumor and microenvironment crosstalk in breast cancer: from biology to therapeutic opportunity.
    Marta Truffi, Serena Mazzucchelli, Ira Ida Skvortsova.
      
    Keywords:  breast cancer; cancer treatment; immunotherapy; prognostic biomarkers; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1339294
  11. 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
  12. Front Pharmacol. 2023 ;14 1303913
    New sights of immunometabolism and agent progress in colitis associated colorectal cancer.
    Jingyue Zhang, Chaoyue Chen, Wei Yan, Yu Fu.
      Colitis associated colorectal cancer is a disease with a high incidence and complex course that develops from chronic inflammation and deteriorates after various immune responses and inflammation-induced attacks. Colitis associated colorectal cancer has the characteristics of both immune diseases and cancer, and the similarity of treatment models contributes to the similar treatment dilemma. Immunometabolism contributes to the basis of life and is the core of many immune diseases. Manipulating metabolic signal transduction can be an effective way to control the immune process, which is expected to become a new target for colitis associated colorectal cancer therapy. Immune cells participate in the whole process of colitis associated colorectal cancer development by transforming their functional condition via changing their metabolic ways, such as glucose, lipid, and amino acid metabolism. The same immune and metabolic processes may play different roles in inflammation, dysplasia, and carcinoma, so anti-inflammation agents, immunomodulators, and agents targeting special metabolism should be used in combination to prevent and inhibit the development of colitis associated colorectal cancer.
    Keywords:  colitis associated colorectal cancer; immune adaption; immunometabolism; inflammation; metabolic reprogramming; metabolites; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1303913
  13. 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
  14. 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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