Dysfunctional T cell metabolism in the tumor microenvironment

Abstract T cells play important roles in anti-tumor immunity. Emerging evidence has revealed that distinct metabolic changes impact the activation and differentiation of T cells. Tailoring immune responses by manipulating cellular metabolic pathways and the identification of new targets may provide new options for cancer immunotherapy. In this review, we focus on recent advances in the metabolic reprogramming of different subtypes of T cells and T cell functions. We summarize how metabolic pathways accurately regulate T cell development, differentiation, and function in the tumor microenvironment. Because of the similar metabolism in activated T cells and tumor cells, we also describe the effect of the tumor microenvironment on T cell metabolism reprogramming, which may provide strategies for maximal anti-cancer effects and enhancing the immunity of T cells. Thus, studies of T lymphocyte metabolism can not only facilitate the basic research of immune metabolism, but also provide potential targets for drug development and new strategies for clinical treatment of cancer.

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Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003217 ◽

2021 ◽

Vol 9 (10) ◽

pp. e003217

Author(s):

Feiya Ma ◽

Jensen Vayalil ◽

Grace Lee ◽

Yuqi Wang ◽

Guangyong Peng

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Tumor Immunity ◽

Cell Metabolism ◽

Immune Checkpoint Blockade ◽

Intrinsic Factors ◽

Cell Dysfunction ◽

T Cell Dysfunction ◽

Immune Checkpoint Blockade Antibodies

Immunotherapeutic drugs including immune checkpoint blockade antibodies have been approved to treat patients in many types of cancers. However, some patients have little or no reaction to the immunotherapy drugs. The mechanisms underlying resistance to tumor immunotherapy are complicated and involve multiple aspects, including tumor-intrinsic factors, formation of immunosuppressive microenvironment, and alteration of tumor and stromal cell metabolism in the tumor microenvironment. T cell is critical and participates in every aspect of antitumor response, and T cell dysfunction is a severe barrier for effective immunotherapy for cancer. Emerging evidence indicates that extracellular vesicles (EVs) secreted by tumor is one of the major factors that can induce T cell dysfunction. Tumor-derived EVs are widely distributed in serum, tissues, and the tumor microenvironment of patients with cancer, which serve as important communication vehicles for cancer cells. In addition, tumor-derived EVs can carry a variety of immune suppressive signals driving T cell dysfunction for tumor immunity. In this review, we explore the potential mechanisms employed by tumor-derived EVs to control T cell development and effector function within the tumor microenvironment. Especially, we focus on current understanding of how tumor-derived EVs molecularly and metabolically reprogram T cell fates and functions for tumor immunity. In addition, we discuss potential translations of targeting tumor-derived EVs to reconstitute suppressive tumor microenvironment or to develop antigen-based vaccines and drug delivery systems for cancer immunotherapy.

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Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy

Cancers ◽

10.3390/cancers12040852 ◽

2020 ◽

Vol 12 (4) ◽

pp. 852 ◽

Cited By ~ 4

Author(s):

Michael F. Coleman ◽

Alyssa J. Cozzo ◽

Alexander J. Pfeil ◽

Suhas K. Etigunta ◽

Stephen D. Hursting

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

T Cell Activation ◽

Cell Activation ◽

Cell Metabolism ◽

Immune Surveillance ◽

Therapy Outcomes ◽

Host Metabolism ◽

The Impact

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction—two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.

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Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

European Journal of Immunology ◽

10.1002/eji.201848058 ◽

2019 ◽

Cited By ~ 6

Author(s):

Helen Carrasco Hope ◽

Robert J. Salmond

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Cell Metabolism

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The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy

eLife ◽

10.7554/elife.55185 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 13

Author(s):

Aaron R Lim ◽

W Kimryn Rathmell ◽

Jeffrey C Rathmell

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Cell Metabolism ◽

Tumor Infiltrating Lymphocytes ◽

T Cell Signaling ◽

Waste Products ◽

Cancer Cell Metabolism ◽

And Function ◽

Infiltrating Lymphocytes

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

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