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Curated Papers > Recent high-impact research on "tumor microenvironment" (IF ≥ 30, last 5 years)

Immunometabolic Interplay in the Tumor Microenvironment. ​

Literature Information ​

DOI10.1016/j.ccell.2020.09.004
PMID33125860
JournalCancer cell
Impact Factor44.5
JCR QuartileQ1
Publication Year2021
Times Cited180
Keywordsimmunology, immunometabolism, in vitro modeling, metabolism, metabolomics
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1535-6108
Pages28-37
Issue39(1)
AuthorsIrem Kaymak, Kelsey S Williams, Jason R Cantor, Russell G Jones

TL;DR ​

This paper explores how the tumor microenvironment (TME) influences the metabolism of immune cells, which in turn affects their differentiation and function. By highlighting recent advancements in metabolic profiling and experimental systems, the authors propose future research directions to understand these metabolic adaptations better, aiming to leverage this knowledge for therapeutic advancements.

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immunology · immunometabolism · in vitro modeling · metabolism · metabolomics

Abstract ​

Immune cells' metabolism influences their differentiation and function. Given that a complex interplay of environmental factors within the tumor microenvironment (TME) can have a profound impact on the metabolic activities of immune, stromal, and tumor cell types, there is emerging interest to advance understanding of these diverse metabolic phenotypes in the TME. Here, we discuss cell-extrinsic contributions to the metabolic activities of immune cells. Then, considering recent technical advances in experimental systems and metabolic profiling technologies, we propose future directions to better understand how immune cells meet their metabolic demands in the TME, which can be leveraged for therapeutic benefit.

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Primary Questions Addressed ​

  1. How do specific environmental factors within the tumor microenvironment alter the metabolic pathways of immune cells?
  2. What role do stromal cells play in modulating the metabolic activities of immune cells in the tumor microenvironment?
  3. Can metabolic profiling technologies identify unique metabolic signatures that predict immune cell behavior in the TME?
  4. How might therapeutic strategies targeting immune cell metabolism improve treatment outcomes in cancer therapy?
  5. What are the implications of metabolic interactions between tumor cells and immune cells for developing new immunotherapies?

Key Findings ​

Research Background and Objectives ​

The tumor microenvironment (TME) significantly influences the metabolic activities of immune cells, stromal cells, and tumor cells. Understanding the immunometabolic interplay in the TME is crucial for developing therapeutic strategies. This study aims to elucidate how various environmental factors affect immune cell metabolism and propose future research directions leveraging recent technological advancements.

Main Methods/Materials/Experimental Design ​

The authors discuss several factors affecting immune cell metabolism within the TME, including nutrient availability, oxygen levels, and intercellular interactions. They emphasize the need for improved experimental models that better mimic the in vivo environment. The proposed technical approaches include:

Mermaid diagram
  1. Nutrient Availability: Examines how different nutrients, such as glucose and amino acids, influence immune cell function.
  2. Oxygen Levels: Discusses the impact of hypoxia on immune responses and metabolism.
  3. Intercellular Interactions: Highlights the complex crosstalk between immune and tumor cells, which can affect metabolic profiles and immune responses.

Key Results and Findings ​

  • Nutrient Limitations: Glucose and amino acid availability can significantly affect the function of tumor-infiltrating lymphocytes (TILs). For instance, glutamine catabolism is crucial for T cell activation, while glucose scarcity can impair effector functions.
  • Hypoxia: The TME often experiences low oxygen levels, which can enhance the inflammatory potential of immune cells and alter their metabolic pathways.
  • Immunomodulatory Metabolites: Waste products like lactate and kynurenine can suppress T cell function and promote immunosuppression in the TME.
  • Metabolic Flexibility: Immune cells, particularly TILs, display metabolic flexibility, adapting to the nutrient availability in the TME, which can influence their persistence and function.

Main Conclusions/Significance/Innovation ​

This perspective highlights the intricate relationship between immune cell metabolism and the TME, emphasizing the importance of understanding these dynamics for developing effective cancer therapies. The authors advocate for the use of more physiologically relevant models to study these interactions, which could lead to better insights into immune responses and tumor progression.

Research Limitations and Future Directions ​

  • Limitations: The study primarily relies on existing literature and conceptual frameworks without presenting new experimental data. There is a need for more direct studies examining metabolic interactions in vivo.
  • Future Directions: The authors suggest further exploration of:
    • Physiological media to better mimic the TME.
    • Advanced imaging techniques to study metabolic profiles in situ.
    • Co-culture systems that incorporate both tumor and immune cells to assess their interactions more accurately.

This comprehensive understanding of immunometabolism in the TME can guide the development of novel therapeutic strategies aimed at enhancing anti-tumor immunity.

References ​

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  2. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. - Gerritje J W van der Windt;Bart Everts;Chih-Hao Chang;Jonathan D Curtis;Tori C Freitas;Eyal Amiel;Edward J Pearce;Erika L Pearce - Immunity (2012)
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  7. Inhibitory effect of tumor cell-derived lactic acid on human T cells. - Karin Fischer;Petra Hoffmann;Simon Voelkl;Norbert Meidenbauer;Julia Ammer;Matthias Edinger;Eva Gottfried;Sabine Schwarz;Gregor Rothe;Sabine Hoves;Kathrin Renner;Birgit Timischl;Andreas Mackensen;Leoni Kunz-Schughart;Reinhard Andreesen;Stefan W Krause;Marina Kreutz - Blood (2007)
  8. Improving the metabolic fidelity of cancer models with a physiological cell culture medium. - Johan Vande Voorde;Tobias Ackermann;Nadja Pfetzer;David Sumpton;Gillian Mackay;Gabriela Kalna;Colin Nixon;Karen Blyth;Eyal Gottlieb;Saverio Tardito - Science advances (2019)
  9. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. - Chih-Hao Chang;Jing Qiu;David O'Sullivan;Michael D Buck;Takuro Noguchi;Jonathan D Curtis;Qiongyu Chen;Mariel Gindin;Matthew M Gubin;Gerritje J W van der Windt;Elena Tonc;Robert D Schreiber;Edward J Pearce;Erika L Pearce - Cell (2015)
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Literatures Citing This Work ​

  1. CRISPR screens in physiologic medium reveal conditionally essential genes in human cells. - Nicholas J Rossiter;Kimberly S Huggler;Charles H Adelmann;Heather R Keys;Ross W Soens;David M Sabatini;Jason R Cantor - Cell metabolism (2021)
  2. ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer. - Jiazhou Liu;Yuxian Wei;Yushen Wu;Jie Li;Jiazheng Sun;Guosheng Ren;Hongzhong Li - Frontiers in immunology (2021)
  3. Immunometabolism of Tissue-Resident Macrophages - An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies. - Giulia Zago;Pedro H V Saavedra;Kayvan R Keshari;Justin S A Perry - Frontiers in immunology (2021)
  4. Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications. - Alice Indini;Francesco Grossi;Mario Mandalà;Daniela Taverna;Valentina Audrito - Biomedicines (2021)
  5. IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment. - Kewei Liu;Ai Huang;Jun Nie;Jun Tan;Shijie Xing;Yue Qu;Ke Jiang - Frontiers in immunology (2021)
  6. Metabolic Interdependency of Th2 Cell-Mediated Type 2 Immunity and the Tumor Microenvironment. - Simon Schreiber;Christoph M Hammers;Achim J Kaasch;Burkhart Schraven;Anne Dudeck;Sascha Kahlfuss - Frontiers in immunology (2021)
  7. High SQLE Expression and Gene Amplification Correlates with Poor Prognosis in Head and Neck Squamous Cell Carcinoma. - Yang Liu;Lijun Fang;Weixian Liu - Cancer management and research (2021)
  8. Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy. - Miljana Nenkov;Yunxia Ma;Nikolaus Gaßler;Yuan Chen - International journal of molecular sciences (2021)
  9. The therapeutic implications of immunosuppressive tumor aerobic glycolysis. - Bradley I Reinfeld;W Kimryn Rathmell;Tae Kon Kim;Jeffrey C Rathmell - Cellular & molecular immunology (2022)
  10. Circadian regulation of cancer cell and tumor microenvironment crosstalk. - Wenjing Xuan;Fatima Khan;Charles David James;Amy B Heimberger;Maciej S Lesniak;Peiwen Chen - Trends in cell biology (2021)

... (170 more literatures)

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