bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–12–22
eight papers selected by
Oltea Sampetrean, Keio University
  1. Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
  2. Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.
  3. Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments.
  4. Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives.
  5. Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.
  6. Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.
  7. IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.
  8. Crosstalk between lactate and tumor-associated immune cells: clinical relevance and insight.
  1. Cell Syst. 2024 Dec 18. pii: S2405-4712(24)00346-6. [Epub ahead of print]15(12): 1225-1244
    Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
    Bing Feng, Rongrong Li, Weilin Li, Li Tang.
      Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.
    Keywords:  CD8(+) T cell; cancer immunotherapy; metabolic immunoengineering
    DOI:  https://doi.org/10.1016/j.cels.2024.11.010
  2. bioRxiv. 2024 Dec 05. pii: 2024.11.29.625709. [Epub ahead of print]
    Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.
    Yijuan Zhang, Li Ling, Swetha Maganti, Jennifer L Hope, Cheska Marie Galapate, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A Scott, Andrew M Lowy, Linda M Bradley, Cosimo Commisso.
      Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact.
    Keywords:  CAF heterogeneity; Metabolic stress; drug delivery; macropinocytosis; pancreatic cancer; stromal architecture; tumor microenvironment
    DOI:  https://doi.org/10.1101/2024.11.29.625709
  3. Curr Opin Immunol. 2024 Dec 12. pii: S0952-7915(24)00101-8. [Epub ahead of print]92 102511
    Navigating the metabolic landscape of regulatory T cells: from autoimmune diseases to tumor microenvironments.
    Janika Härm, Yu-Tong Fan, Dirk Brenner.
      Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, playing crucial roles in modulating autoimmune conditions and contributing to the suppressive tumor microenvironment. Their cellular metabolism governs their generation, stability, proliferation, and suppressive function. Enhancing Treg metabolism to boost their suppressive function offers promising therapeutic potential for alleviating inflammatory symptoms in autoimmune diseases. Conversely, inhibiting Treg metabolism to reduce their suppressive function can enhance the efficacy of traditional immunotherapy in cancer patients. This review explores recent advances in targeting Treg metabolism in autoimmune diseases and the metabolic adaptations of Tregs within the tumor microenvironment that increase their immunosuppressive function.
    DOI:  https://doi.org/10.1016/j.coi.2024.102511
  4. Cancers (Basel). 2024 Dec 06. pii: 4094. [Epub ahead of print]16(23):
    Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives.
    Ari Hashimoto, Shigeru Hashimoto.
      Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.
    Keywords:  ARF6; Arid5a; PDAC; metabolic reprogramming; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers16234094
  5. Biochim Biophys Acta Mol Basis Dis. 2024 Dec 15. pii: S0925-4439(24)00623-9. [Epub ahead of print]1871(3): 167629
    Immunometabolism in head and neck squamous cell carcinoma: Hope and challenge.
    Yi-Jia-Ning Zhang, Yao Xiao, Zi-Zhan Li, Lin-Lin Bu.
      Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.
    Keywords:  Head and neck squamous cell carcinoma; Immunometabolism; Immunotherapy; Prognosis
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167629
  6. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2412070121
    Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.
    Heng Wang, Fang Xu, Chenlu Yao, Huaxing Dai, Jialu Xu, Bingbing Wu, Bo Tian, Xiaolin Shi, Chao Wang.
      Inhibiting indoleamine 2,3 dioxygenase (IDO) for anticancer therapy has garnered significant attention in recent years. However, current IDO inhibitors face significant challenges which limit their clinical application. Here, we genetically engineered a high tryptophan-expressing Clostridium butyricum (L-Trp CB) strain that can colonize tumors strictly following systemic administration. We revealed that butyrate produced by L-Trp CB can inhibit IDO activity, preventing tryptophan catabolism and kynurenine accumulation in tumors. In addition, the large released tryptophan by L-Trp CB can provide discrete signals that support CD8+ T cell activation and energy metabolism within the tumor microenvironment. We observed that L-Trp CB significantly restored the proportion and function of CD8+ T cells, leading to significantly delayed tumor growth in both mouse and rabbit multiple tumor models with limited side effects. We here provide a synthetic biology treatment strategy for enhanced tumor immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response in tumors.
    Keywords:  IDO; T cell response; engineering bacteria; synthetic biology; tryptophan
    DOI:  https://doi.org/10.1073/pnas.2412070121
  7. bioRxiv. 2024 Dec 05. pii: 2024.12.02.626426. [Epub ahead of print]
    IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.
    Triantafyllia Karakousi, Vanessa Cristaldi, Maria Luiza Lopes de Oliveira, Luiz Henrique Medeiros Geraldo, Tania J González-Robles, Gabrielle da Silva, Alec P Breazeale, Joel Encarnacion-Rosado, Joanna Pozniak, Alec C Kimmelman, Kelly V Ruggles, J Chris Marine, Navdeep S Chandel, Amanda W Lund.
      Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We find that in mice and humans, intratumoral lymphatic vessel density negatively correlates with productive cytotoxic immune responses and identify IFNγ as an intrinsic inhibitor of lymphangiogenesis. Specific deletion of the Ifngr1 in lymphatic endothelial cells (LECs) greatly expanded the intratumoral lymphatic network and drove the emergence of a tip-like endothelial state, promoting lymph node metastasis but not dendritic cell migration. IFNγ inhibits oxidative phosphorylation, which is required for proliferation and acquisition of the pathologic transcriptional state. Our data indicate that IFNγ induces a phenotypic switch in tumor-associated lymphatic vessels to reinforce canonical immune surveillance and block metastasis.
    DOI:  https://doi.org/10.1101/2024.12.02.626426
  8. Front Oncol. 2024 ;14 1506849
    Crosstalk between lactate and tumor-associated immune cells: clinical relevance and insight.
    Kemin Sun, Ye Shen, Xiang Xiao, Hao Xu, Quanli Zhang, Ming Li.
      Lactate, which was traditionally viewed as a metabolic byproduct of anaerobic glycolysis, has emerged as a significant signaling molecule involved in the development of tumors. Current studies highlight its dual function, where it not only fuels tumor development but also modulates immune responses. Lactate has an effect on various tumor-associated immune cells, promoting immunosuppressive conditions that facilitate tumor growth and immune evasion. This phenomenon is strongly associated with the Warburg effect, a metabolic shift observed in many cancers that favors glycolysis over oxidative phosphorylation, resulting in elevated lactate production. Exploring the complex interplay between lactate metabolism and tumor immunity provides a novel understanding regarding the mechanisms of tumor immune evasion and resistance to therapies. This review discusses the unique biology of lactate in the TME, its impact on immune cell dynamics, and its potential as a tumor treatment target.
    Keywords:  Warburg effect; cancer immunotherapy; immunosuppression; lactate; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2024.1506849
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