bims-mecami 2024-05-12 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–05–12
thirteen papers selected by
Oltea Sampetrean, Keio University

Fructose-induced metabolic reprogramming of cancer cells.
Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
The role of tumor-associated macrophages in tumor immune evasion.
Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer.
Single-cell analyses reveal the metabolic heterogeneity and plasticity of the tumor microenvironment during head and neck squamous cell carcinoma progression.
Reprogrammed mitochondria: a central hub of cancer cell metabolism.
GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
Tuning Cellular Metabolism for Cancer Virotherapy.
Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.
Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.
Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
Havoc in harmony: Unravelling the intricacies of angiogenesis orchestrated by the tumor microenvironment.
Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.

Front Immunol. 2024 ;15 1375461

Fructose-induced metabolic reprogramming of cancer cells.

Kenneth K Y Ting.

  Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.

Keywords:  GLUT5; cancer; fructose; glycolysis; ketohexokinase (KHK); metabolic reprogramming; metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2024.1375461
Cell Metab. 2024 May 07. pii: S1550-4131(24)00127-X. [Epub ahead of print]36(5): 884-886

Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.

Qiang Cai, Yihao Tian, Quazi T H Shubhra.

Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.

DOI: https://doi.org/10.1016/j.cmet.2024.04.007
J Cancer Res Clin Oncol. 2024 May 07. 150(5): 238

The role of tumor-associated macrophages in tumor immune evasion.

Ruizhe Huang, Ting Kang, Siyu Chen.

   BACKGROUND: Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME.
METHODS: We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs.
RESULTS: TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.

Keywords:  Immune evasion; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s00432-024-05777-4
Nat Commun. 2024 May 07. 15(1): 3837

Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer.

Kang Wang, Ioannis Zerdes, Henrik J Johansson, Dhifaf Sarhan, Yizhe Sun, Dimitris C Kanellis, Emmanouil G Sifakis, Artur Mezheyeuski, Xingrong Liu, Niklas Loman, Ingrid Hedenfalk, Jonas Bergh, Jiri Bartek, Thomas Hatschek, Janne Lehtiö, Alexios Matikas, Theodoros Foukakis.

Although metabolic reprogramming within tumor cells and tumor microenvironment (TME) is well described in breast cancer, little is known about how the interplay of immune state and cancer metabolism evolves during treatment. Here, we characterize the immunometabolic profiles of tumor tissue samples longitudinally collected from individuals with breast cancer before, during and after neoadjuvant chemotherapy (NAC) using proteomics, genomics and histopathology. We show that the pre-, on-treatment and dynamic changes of the immune state, tumor metabolic proteins and tumor cell gene expression profiling-based metabolic phenotype are associated with treatment response. Single-cell/nucleus RNA sequencing revealed distinct tumor and immune cell states in metabolism between cold and hot tumors. Potential drivers of NAC based on above analyses were validated in vitro. In summary, the study shows that the interaction of tumor-intrinsic metabolic states and TME is associated with treatment outcome, supporting the concept of targeting tumor metabolism for immunoregulation.

DOI: https://doi.org/10.1038/s41467-024-47932-y
Cancer Res. 2024 May 08.

Single-cell analyses reveal the metabolic heterogeneity and plasticity of the tumor microenvironment during head and neck squamous cell carcinoma progression.

Xiaoyan Meng, Yang Zheng, Lingfang Zhang, Peipei Liu, Zhonglong Liu, Yue He.

Metabolic reprogramming is a hallmark of cancer. In addition to metabolic alterations in the tumor cells, multiple other metabolically active cell types in the tumor microenvironment (TME) contribute to the emergence of a tumor-specific metabolic milieu. Here, we defined the metabolic landscape of the TME during progression of head and neck squamous cell carcinoma (HNSCC) by performing single-cell RNA sequencing (scRNA-seq) on 26 human patient specimens, including normal tissue, pre-cancerous lesions, early-stage cancer, advanced-stage cancer, lymph node metastases, and recurrent tumors. The analysis revealed substantial heterogeneity at the transcriptional, developmental, metabolic, and functional levels in different cell types. SPP1+ macrophages were identified as a pro-tumor and pro-metastatic macrophage subtype with high fructose and mannose metabolism, which was further substantiated by integrative analysis and validation experiments. An inhibitor of fructose metabolism reduced the proportion of SPP1+ macrophages, reshaped the immunosuppressive TME, and suppressed tumor growth. In conclusion, this work delineated the metabolic landscape of HNSCC at a single-cell resolution and identified fructose metabolism as a key metabolic feature of a pro-tumor macrophage subpopulation.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1344
Biochem Soc Trans. 2024 May 08. pii: BST20231090. [Epub ahead of print]

Reprogrammed mitochondria: a central hub of cancer cell metabolism.

Fabio Ciccarone, Maria Rosa Ciriolo.

  Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of specialized products, cancer cells have to rewire the metabolic constraints imposed by the differentiation process. They need to balance the bioenergetic supply with the anabolic requirements that entail the intense proliferation rate, including nucleotide and membrane lipid biosynthesis. For this aim, mitochondrial metabolism is reprogrammed following the activation of specific oncogenic pathways or due to specific mutations of mitochondrial proteins. The main process leading to mitochondrial metabolic rewiring is the alteration of the tricarboxylic acid cycle favoring the appropriate orchestration of anaplerotic and cataplerotic reactions. According to the tumor type or the microenvironmental conditions, mitochondria may decouple glucose catabolism from mitochondrial oxidation in favor of glutaminolysis or disable oxidative phosphorylation for avoiding harmful production of free radicals. These and other metabolic settings can be also determined by the neo-production of oncometabolites that are not specific for the tissue of origin or the accumulation of metabolic intermediates able to boost pro-proliferative metabolism also impacting epigenetic/transcriptional programs. The full characterization of tumor-specific mitochondrial signatures may provide the identification of new biomarkers and therapeutic opportunities based on metabolic approaches.

Keywords:  TCA cycle; metabolic disorders; mitochondrial dysfunction

DOI:  https://doi.org/10.1042/BST20231090
Mol Ther. 2024 May 07. pii: S1525-0016(24)00303-4. [Epub ahead of print]

GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.

Yuzhe Shi, Ivan S Kotchetkov, Anton Dobrin, Sophie A Hanina, Vinagolu K Rajasekhar, John H Healey, Michel Sadelain.

The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Rα2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.

DOI: https://doi.org/10.1016/j.ymthe.2024.05.006
Cancer Lett. 2024 May 06. pii: S0304-3835(24)00317-3. [Epub ahead of print] 216924

Tuning Cellular Metabolism for Cancer Virotherapy.

Dian Xiong, Qing Wang, Wei-Ming Wang, Zhi-Jun Sun.

  Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance.

Keywords:  Cancer immunotherapy; Cancer metabolism; Immune cell metabolism; Immunosuppressive tumor microenvironment; Oncolytic viruses

DOI:  https://doi.org/10.1016/j.canlet.2024.216924
Int J Biol Sci. 2024 ;20(7): 2779-2789

Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.

Rui Liang, Aoyu Cheng, Shengxin Lu, Xiaokun Zhang, Maomao Ren, Jiayi Lin, Ye Wu, Weidong Zhang, Xin Luan.

  Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.

Keywords:  Cancer; Immunotherapy; Metabolic reprogramming; Selenium; Seleno-amino acid

DOI:  https://doi.org/10.7150/ijbs.95484
Cell. 2024 May 02. pii: S0092-8674(24)00410-0. [Epub ahead of print]

Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.

Chen Wang, Qun Zeng, Zeynep Melis Gül, Sisi Wang, Robert Pick, Phil Cheng, Ruben Bill, Yan Wu, Stefan Naulaerts, Coline Barnoud, Pei-Chun Hsueh, Sofie Hedlund Moller, Mara Cenerenti, Mengzhu Sun, Ziyang Su, Stéphane Jemelin, Volodymyr Petrenko, Charna Dibner, Stéphanie Hugues, Camilla Jandus, Zhongwu Li, Olivier Michielin, Ping-Chih Ho, Abhishek D Garg, Federico Simonetta, Mikaël J Pittet, Christoph Scheiermann.

  The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

Keywords:  BMAL1; CAR T therapy; PD-1; chronotherapy; circadian; immune checkpoint blockade; immunology; melanoma; tumor-infiltrating leukocyte

DOI:  https://doi.org/10.1016/j.cell.2024.04.015
Immunity. 2024 Apr 30. pii: S1074-7613(24)00211-5. [Epub ahead of print]

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Alessandra De Leo, Alessio Ugolini, Xiaoqing Yu, Fabio Scirocchi, Delia Scocozza, Barbara Peixoto, Angelica Pace, Luca D'Angelo, James K C Liu, Arnold B Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A Vogelbaum, Jose R Conejo-Garcia, Paulo C Rodriguez, Filippo Veglia.

  Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Keywords:  ER stress; PERK; brain cancer; glioblastoma; glycolysis; histone lactylation; immunosuppression; metabolism; myeloid cells; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.immuni.2024.04.006
Cancer Treat Rev. 2024 May 01. pii: S0305-7372(24)00077-X. [Epub ahead of print]127 102749

Havoc in harmony: Unravelling the intricacies of angiogenesis orchestrated by the tumor microenvironment.

Sushree Subhadra Acharya, Chanakya Nath Kundu.

  Cancer cells merely exist in isolation; rather, they exist in an intricate microenvironment composed of blood vessels, signalling molecules, immune cells, stroma, fibroblasts, and the ECM. The TME provides a setting that is favourable for the successful growth and survivance of tumors. Angiogenesis is a multifaceted process that is essential for the growth, invasion, and metastasis of tumors. TME can be visualized as a "concert hall," where various cellular and non-cellular factors perform in a "symphony" to orchestrate tumor angiogenesis and create "Havoc" instead of "Harmony". In this review, we comprehensively summarized the involvement of TME in regulating tumor angiogenesis. Especially, we have focused on immune cells and their secreted factors, inflammatory cytokines and chemokines, and their role in altering the TME. We have also deciphered the crosstalk among various cell types that further aids the process of tumor angiogenesis. Additionally, we have highlighted the limitations of existing anti-angiogenic therapy and discussed various potential strategies that could be used to overcome these challenges and improve the efficacy of anti-angiogenic therapy.

Keywords:  Cytokines; Immune cells; Oncoimmunology; Tumor angiogenesis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctrv.2024.102749
Front Cell Dev Biol. 2024 ;12 1387198

Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.

Yuexin Xu, Chris P Miller, Scott S Tykodi, Shreeram Akilesh, Edus H Warren.

  Tumor-associated endothelial cells (TECs) are crucial mediators of immune surveillance and immune escape in the tumor microenvironment (TME). TECs driven by angiogenic growth factors form an abnormal vasculature which deploys molecular machinery to selectively promote the function and recruitment of immunosuppressive cells while simultaneously blocking the entry and function of anti-tumor immune cells. TECs also utilize a similar set of signaling regulators to promote the metastasis of tumor cells. Meanwhile, the tumor-infiltrating immune cells further induce the TEC anergy by secreting pro-angiogenic factors and prevents further immune cell penetration into the TME. Understanding the complex interactions between TECs and immune cells will be needed to successfully treat cancer patients with combined therapy to achieve vasculature normalization while augmenting antitumor immunity. In this review, we will discuss what is known about the signaling crosstalk between TECs and tumor-infiltrating immune cells to reveal insights and strategies for therapeutic targeting.

Keywords:  angiogenesis; immune cell transmigration; immune suppression; tumor endothelial cell; tumor microenvironment across the tumor endothelium

DOI:  https://doi.org/10.3389/fcell.2024.1387198