bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–12–10
fifteen papers selected by
Oltea Sampetrean, Keio University



  1. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00415-1. [Epub ahead of print]35(12): 2093-2094
      Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang et al. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ T cells for improved tumor control.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.004
  2. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01530-9. [Epub ahead of print]42(12): 113518
      The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113518
  3. Arch Pharm Res. 2023 Dec 07.
      The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.
    Keywords:  Cholesterol transport; Lipid uptake; Lipogenesis; Lipolysis; Phytochemical; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12272-023-01473-y
  4. Sci Adv. 2023 Dec 08. 9(49): eadf9522
      Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adf9522
  5. Front Oncol. 2023 ;13 1251355
      Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.
    Keywords:  Th1 and Th2 response; antitumoral response; helminth infection; immune evasion; immunometabolism
    DOI:  https://doi.org/10.3389/fonc.2023.1251355
  6. Adv Immunol. 2023 ;pii: S0065-2776(23)00032-9. [Epub ahead of print]160 83-116
      Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.
    DOI:  https://doi.org/10.1016/bs.ai.2023.10.002
  7. APL Bioeng. 2023 Dec;7(4): 046116
      Breast cancer metastasis is initiated by invasion of tumor cells into the collagen type I-rich stroma to reach adjacent blood vessels. Prior work has identified that metabolic plasticity is a key requirement of tumor cell invasion into collagen. However, it remains largely unclear how blood vessels affect this relationship. Here, we developed a microfluidic platform to analyze how tumor cells invade collagen in the presence and absence of a microvascular channel. We demonstrate that endothelial cells secrete pro-migratory factors that direct tumor cell invasion toward the microvessel. Analysis of tumor cell metabolism using metabolic imaging, metabolomics, and computational flux balance analysis revealed that these changes are accompanied by increased rates of glycolysis and oxygen consumption caused by broad alterations of glucose metabolism. Indeed, restricting glucose availability decreased endothelial cell-induced tumor cell invasion. Our results suggest that endothelial cells promote tumor invasion into the stroma due, in part, to reprogramming tumor cell metabolism.
    DOI:  https://doi.org/10.1063/5.0171109
  8. Sci Adv. 2023 Dec 08. 9(49): eadm6816
      Inhibiting a key metabolic enzyme, ACLY, in cancer cells impacts T cell function in immunotherapy-resistant tumors and may offer a target for therapeutic treatment.
    DOI:  https://doi.org/10.1126/sciadv.adm6816
  9. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01519-X. [Epub ahead of print]42(12): 113507
      The expression of pro-lymphangiogenic VEGF-C in primary tumors is associated with sentinel lymph node metastasis in most solid cancer types. However, the impact of VEGF-C on distant organ metastasis remains unclear. Perivascular tumor-associated macrophages (TAMs) play a crucial role in guiding hematogenous spread of cancer cells by establishing metastatic pathways within the tumor microenvironment. This process supports breast cancer cell intravasation and metastatic dissemination. We show here that VEGF-C-expressing TAMs reduce the dissemination of mammary cancer cells to the lungs while concurrently increasing lymph node metastasis. These TAMs express podoplanin and interact with normalized tumor blood vessels expressing VEGFR3. Moreover, clinical data suggest inverse association between VEGF-C-expressing TAMs and breast cancer malignancy. Thus, our study elucidates the paradoxical role of VEGF-C-expressing TAMs in redirecting cancer cells to preferentially disseminate to lymph nodes rather than to lungs, partially achieved by normalizing tumor blood vessels and promoting lymphangiogenesis.
    Keywords:  CP: Cancer; VEGFR3; breast cancer; hematogenous cancer cell spreading; hypoxia; lymph node metastases; podoplanin; tumor microenvironment of metastasis; tumor-associated macrophages; vascular endothelial growth factor-C; vascular normalization
    DOI:  https://doi.org/10.1016/j.celrep.2023.113507
  10. J Immunother Cancer. 2023 Dec 06. pii: e008081. [Epub ahead of print]11(12):
       BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer.
    METHODS: The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs.
    RESULTS: Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy.
    CONCLUSION: These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.
    Keywords:  Immune Checkpoint Inhibitors; Immunotherapy; Metabolic Networks and Pathways; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2023-008081
  11. Curr Opin Biotechnol. 2023 Dec 05. pii: S0958-1669(23)00132-5. [Epub ahead of print]85 103022
      Amino acid transporters (AATs) facilitate nutrient uptake and nutrient exchange between cancer and stromal cells. The posttranslational modification (PTM) of transporters is an important mechanism that tumor-associated cells use to dynamically regulate their function and stability in response to microenvironmental cues. In this review, we summarize recent findings that demonstrate the significance of N-glycosylation, phosphorylation, and ubiquitylation for the function of AATs. We also highlight powerful approaches that hijack the PTM machinery that could be used as therapeutics or tools to modulate transporter activity.
    DOI:  https://doi.org/10.1016/j.copbio.2023.103022
  12. Neoplasma. 2023 Oct;pii: 230704N348. [Epub ahead of print]70(5):
      High cholesterol is an important factor inducing colorectal cancer (CRC). The study aims to determine the key genes and regulatory mechanism associated with tumor-infiltrating T cells underlying cholesterol-induced CRC. Gene expression data and clinical data from CRCS in The Cancer Genome Atlas (TCGA) were selected for differential expression and survival analysis. A total of 5,815 DEGs and 21 cholesterol-associated KEGG pathways were identified. Subsequently, 128 CRCs and 127 patients without obvious intestinal lesions were recruited to analyze the relationship between GPX3 expression, cholesterol levels, and pathologic condition. The results showed that the expression of cholesterol-related gene GPX3 was negatively associated with cholesterol level, but positively correlated with Ki-67 proliferation index in CRC. The expression of GPX3 was higher in CRC patients who were in poorly differentiated and advanced stage. In addition, a mice model of high-cholesterol diet intervention was constructed to detect the levels of cholesterol and GPX3 in the peripheral blood of mice, and it was found that the expression level of GPX3 in high-cholesterol mice was lower than that in normal diet mice. CD8+ T cells were isolated from the spleen of mice and the T cell surface receptors were detected. It was found that the expression of CD69 in CD8+ T cells of mice interfered with the high-cholesterol diet, while the expression of PD1, TIM-3, and CTLA-4 was increased. CD8+ T cells were co-cultured with MC38 cells to detect the proliferation rate of CRC cells. The results showed that the tumor cell proliferation ratio in the high cholesterol group was higher than that in the control group. Furthermore, GPX3 downstream genes associated with m6A modification and tumor-infiltrating T cells were screened, and a T cell immune-related ceRNA network was constructed. In total, 53 GPX3 downstream genes associated with m6A modification and tumor-infiltrating T cells were identified. A PPI network that contained 45 nodes and 85 interaction pairs was constructed. The ceRNA network, including 39 miRNA-target and 43 lncRNA-miRNA regulatory pairs, was constructed. In conclusion, GPX3 is a potential target for cholesterol regulation of T cell immunity in CRC.
    DOI:  https://doi.org/10.4149/neo_2023_230704N348
  13. Hepatology. 2023 Dec 05.
       BACKGROUND AIMS: Crosstalk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor hepatocellular carcinogenesis (HCC). However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC.
    APPROACH RESULTS: We found that ALDOB downregulation was negatively correlated with CD8+ T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-β expression, thereby increasing the number of Treg cells and impairing the activity of CD8+ T cells. Consistently, a combination of low ALDOB and high TGF-β expression exhibited the worst overall survival for HCC patients. More importantly, the simultaneous blocking of TGF-β and PD-1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A (KAT2A), leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of KAT2A activity by small molecule inhibitors suppressed TGF-β and HCC.
    CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-β signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.
    DOI:  https://doi.org/10.1097/HEP.0000000000000704
  14. Leukemia. 2023 Dec 06.
      Chronic lymphocytic leukemia (CLL) is still an incurable disease, with many patients developing resistance to conventional and targeted therapies. To better understand the physiology of CLL and facilitate the development of innovative treatment options, we examined specific metabolic features in the tumor CLL B-lymphocytes. We observed metabolic reprogramming, characterized by a high level of mitochondrial oxidative phosphorylation activity, a low glycolytic rate, and the presence of C2- to C6-carnitine end-products revealing an unexpected, essential role for peroxisomal fatty acid beta-oxidation (pFAO). Accordingly, downmodulation of ACOX1 (a rate-limiting pFAO enzyme overexpressed in CLL cells) was enough to shift the CLL cells' metabolism from lipids to a carbon- and amino-acid-based phenotype. Complete blockade of ACOX1 resulted in lipid droplet accumulation and caspase-dependent death in CLL cells, including those from individuals with poor cytogenetic and clinical prognostic factors. In a therapeutic translational approach, ACOX1 inhibition spared non-tumor blood cells from CLL patients but led to the death of circulating, BCR-stimulated CLL B-lymphocytes and CLL B-cells receiving pro-survival stromal signals. Furthermore, a combination of ACOX1 and BTK inhibitors had a synergistic killing effect. Overall, our results highlight a less-studied but essential metabolic pathway in CLL and pave the way towards the development of new, metabolism-based treatment options.
    DOI:  https://doi.org/10.1038/s41375-023-02103-8
  15. Metabolism. 2023 Nov 30. pii: S0026-0495(23)00351-7. [Epub ahead of print]151 155747
      Reactive oxygen species (ROS) are a group of short-lived highly reactive molecules formed intracellularly from molecular oxygen. ROS can alter biochemical, transcriptional, and epigenetic programs and have an indispensable role in cellular function. In immune cells, ROS are mediators of specialized functions such as phagocytosis, antigen presentation, activation, cytolysis, and differentiation. ROS have a fundamental role in the tumor microenvironment (TME) where they are produced by immune cell-intrinsic and -extrinsic mechanisms. ROS can act as a double-edged sword with short exposures leading to activation in various innate and adaptative immune cells, and prolonged exposures, unopposed by redox balancing antioxidants leading to exhaustion, immunosuppression, and unresponsiveness to cancer immunotherapy. Due to its plasticity and impact on the anti-tumor function of immune cells, attempts are currently in process to harness ROS biology with the purpose to improve contemporary strategies of cancer immunotherapy. Here, we provide a short overview how ROS and various antioxidant systems impact on the function of innate and adaptive immune system cells with emphasis on the TME and immune-based therapies for cancer.
    Keywords:  Immune cells; Reactive oxygen species; cancer immunotherapy; cancer microenvironment
    DOI:  https://doi.org/10.1016/j.metabol.2023.155747