bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–04–07
eight papers selected by
Oltea Sampetrean, Keio University
  1. Tumor-Host Cometabolism Collaborates to Shape Cancer Immunity.
  2. Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment.
  3. B7-H3 suppresses CD8+ T cell immunologic function through reprogramming glycolytic metabolism.
  4. Metabolic Modulation of Kynurenine Based on Kynureninase-Loaded Nanoparticle Depot Overcomes Tumor Immune Evasion in Cancer Immunotherapy.
  5. Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.
  6. Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis.
  7. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.
  8. Cancer immunometabolism: advent, challenges, and perspective.
  1. Cancer Discov. 2024 Apr 04. 14(4): 653-657
    Tumor-Host Cometabolism Collaborates to Shape Cancer Immunity.
    Yingcheng Wu, Qiang Zou, Peng Jiang, Qiang Gao.
       SUMMARY: Nutrients are essential for supporting tumor growth and immune cell function in the tumor microenvironment, but emerging evidence reveals a paradoxical competition and collaboration between the metabolic demands of proliferating cancer cells and immune cell activation. Dietary interventions and metabolic immunoengineering offer promise to selectively modulate cancer and immune cell metabolism by targeting metabolic sensing processes rather than pathways directly, moving beyond conventional ideas and heralding an exciting new era of immunometabolism discovery and translation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1509
  2. Anim Cells Syst (Seoul). 2024 ;28(1): 123-136
    Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment.
    Seung Woo Kim, Chan Woo Kim, Young-Ah Moon, Hong Seok Kim.
      The tumor microenvironment comprises both tumor and non-tumor stromal cells, including tumor-associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts. TAMs, major components of non-tumor stromal cells, play a crucial role in creating an immunosuppressive environment by releasing cytokines, chemokines, growth factors, and immune checkpoint proteins that inhibit T cell activity. During tumors develop, cancer cells release various mediators, including chemokines and metabolites, that recruit monocytes to infiltrate tumor tissues and subsequently induce an M2-like phenotype and tumor-promoting properties. Metabolites are often overlooked as metabolic waste or detoxification products but may contribute to TAM polarization. Furthermore, macrophages display a high degree of plasticity among immune cells in the tumor microenvironment, enabling them to either inhibit or facilitate cancer progression. Therefore, TAM-targeting has emerged as a promising strategy in tumor immunotherapy. This review provides an overview of multiple representative metabolites involved in TAM phenotypes, focusing on their role in pro-tumoral polarization of M2.
    Keywords:  Cancer; TAM; metabolites; polarization; tumor microenvironment
    DOI:  https://doi.org/10.1080/19768354.2024.2336249
  3. J Cancer. 2024 ;15(9): 2505-2517
    B7-H3 suppresses CD8+ T cell immunologic function through reprogramming glycolytic metabolism.
    Yulu Wu, Wenzhe Han, Xiufa Tang, Jiyuan Liu, Zhiyong Guo, Zhangao Li, Chenchen Cai, Lin Que.
      Malignant neoplasms pose a formidable threat to human well-being. Prior studies have documented the extensive expression of B7 homolog 3 (B7-H3 or CD276) across various tumors, affecting glucose metabolism. Yet, the link between metabolic modulation and immune responses remains largely unexplored. Our study reveals a significant association between B7-H3 expression and advanced tumor stages, lymph node metastasis, and tumor location in oral squamous cell carcinoma (OSCC). We further elucidate B7-H3's role in mediating glucose competition between cancer cells and CD8+ T cells. Through co-culturing tumor cells with flow cytometry-sorted CD8+ T cells, we measured glucose uptake and lactate secretion in both cell types. Additionally, we assessed interferon-gamma (IFN-γ) release and the immune and exhaustion status of CD8+ T cells. Our findings indicate that B7-H3 enhances glycolysis in OSCC and malignant melanoma, while simultaneously inhibiting CD8+ T cell glycolysis. Silencing B7-H3 led to increased IFN-γ secretion in co-cultures, highlighting its significant role in modulating CD8+ T cell functions within the tumor microenvironment and its impact on tumorigenicity. We also demonstrate that glycolysis inhibition can be mitigated by exogenous glucose supplementation. Mechanistically, our study suggests B7-H3's influence on metabolism might be mediated through the phosphoinositide3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway. This research unveils how B7-H3 affects immune functions via metabolic reprogramming.
    DOI:  https://doi.org/10.7150/jca.90819
  4. ACS Appl Mater Interfaces. 2024 Apr 04.
    Metabolic Modulation of Kynurenine Based on Kynureninase-Loaded Nanoparticle Depot Overcomes Tumor Immune Evasion in Cancer Immunotherapy.
    Se-Youl Chae, Hojeong Shin, Jiwon Woo, Seounghun Kang, Soo Min Lee, Dal-Hee Min.
      Evading recognition of immune cells is a well-known strategy of tumors used for their survival. One of the immune evasion mechanisms is the synthesis of kynurenine (KYN), a metabolite of tryptophan, which suppresses the effector T cells. Therefore, lowering the KYN concentration can be an efficient antitumor therapy by restoring the activity of immune cells. Recently, kynureninase (KYNase), which is an enzyme transforming KYN into anthranilate, was demonstrated to show the potential to decrease KYN concentration and inhibit tumor growth. However, due to the limited bioavailability and instability of proteins in vivo, it has been challenging to maintain the KYNase concentration sufficiently high in the tumor microenvironment (TME). Here, we developed a nanoparticle system loaded with KYNase, which formed a Biodegradable and Implantable Nanoparticle Depot named 'BIND' following subcutaneous injection. The BIND sustainably supplied KYNase around the TME while located around the tumor, until it eventually degraded and disappeared. As a result, the BIND system enhanced the proliferation and cytokine production of effector T cells in the TME, followed by tumor growth inhibition and increased mean survival. Finally, we showed that the BIND carrying KYNase significantly synergized with PD-1 blockade in three mouse models of colon cancer, breast cancer, and melanoma.
    Keywords:  cancer immunotherapy; drug delivery; immune evasion; kynureninase; nanomedicine
    DOI:  https://doi.org/10.1021/acsami.4c00513
  5. Cancer Cell. 2024 Mar 31. pii: S1535-6108(24)00090-4. [Epub ahead of print]
    Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.
    Ningning Niu, Xuqing Shen, Zheng Wang, Yueyue Chen, Yawen Weng, Feier Yu, Yingying Tang, Ping Lu, Mingzhu Liu, Liwei Wang, Yongwei Sun, Minwei Yang, Baiyong Shen, Jiabin Jin, Zipeng Lu, Kuirong Jiang, Yufeng Shi, Jing Xue.
      The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.
    Keywords:  OXPHOS; Pancreatic cancer; SETD2; cell communication; epigenetic dysregulation; lipid-laden CAF
    DOI:  https://doi.org/10.1016/j.ccell.2024.03.005
  6. Mol Metab. 2024 Apr 01. pii: S2212-8778(24)00061-9. [Epub ahead of print] 101930
    Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis.
    Camille Lefevre, Morgane M Thibaut, Audrey Loumaye, Jean-Paul Thissen, Audrey M Neyrinck, Benoit Navez, Nathalie M Delzenne, Olivier Feron, Laure B Bindels.
       OBJECTIVE: Tumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia.
    METHODS: To evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes.
    RESULTS: Here, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocyte and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for β-glucuronidase as a promising new actor in adipocyte lipolysis.
    CONCLUSIONS: Tumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for dual therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.
    Keywords:  Adipocytes; Adipose tissue; Beta-glucuronidase; Cancer cachexia; Lipolysis; Tumor acidosis
    DOI:  https://doi.org/10.1016/j.molmet.2024.101930
  7. Cell. 2024 Mar 28. pii: S0092-8674(24)00303-9. [Epub ahead of print]
    Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.
    Tianyu Cao, Wenyao Zhang, Qi Wang, Chen Wang, Wanqi Ma, Cangang Zhang, Minghui Ge, Miaomiao Tian, Jia Yu, Anjun Jiao, Liang Wang, Manjiao Liu, Pei Wang, Zhiyu Guo, Yun Zhou, Shuyi Chen, Wen Yin, Jing Yi, Hao Guo, Hua Han, Baojun Zhang, Kaichun Wu, Daiming Fan, Xin Wang, Yongzhan Nie, Yuanyuan Lu, Xiaodi Zhao.
      Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.
    Keywords:  ATF4; ER stress; T cell exhaustion; chemoresistance; gastric cancer; immune checkpoint; solute carrier; taurine; transcription regulation; tumor recurrence and metastasis
    DOI:  https://doi.org/10.1016/j.cell.2024.03.011
  8. Mol Cancer. 2024 Apr 05. 23(1): 72
    Cancer immunometabolism: advent, challenges, and perspective.
    Qin Dang, Borui Li, Bing Jin, Zeng Ye, Xin Lou, Ting Wang, Yan Wang, Xuan Pan, Qiangsheng Hu, Zheng Li, Shunrong Ji, Chenjie Zhou, Xianjun Yu, Yi Qin, Xiaowu Xu.
      For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.
    Keywords:  Cancer-immunity cycle; Cancer-immunometabolism subcycle; Immunity; Immunometabolism; Metabolic adaptation; Metabolic reprogramming
    DOI:  https://doi.org/10.1186/s12943-024-01981-5
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