scholarly journals Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Zhongping Yin ◽  
Ling Bai ◽  
Wei Li ◽  
Tanlun Zeng ◽  
Huimin Tian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Metabolic Pathways ◽  
Cell Metabolism ◽  
Basic Research ◽  
Metabolic Reprogramming ◽  
Activated T Cells ◽  
Cell Functions ◽  
Anti Cancer

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.

scholarly journals The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity

2021 ◽  
Vol 69 (1) ◽  
Author(s):  
Helen Carrasco Hope ◽  
Robert J. Salmond
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Metabolic Pathways ◽  
Cell Metabolism ◽  
Building Blocks ◽  
Essential Amino Acids ◽  
Metabolic Reprogramming ◽  
Tumour Immunity

AbstractT cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain proliferation and effector responses. Amino acids are key nutrients for T cells and have essential roles as building blocks for protein synthesis as well as in numerous metabolic pathways. In this review, we discuss the roles for uptake and biosynthesis of non-essential amino acids in T cell metabolism, activation and effector function. Furthermore, we highlight the effects of amino acid metabolism and depletion by cancer cells on T cell anti-tumour function and discuss approaches to modulate and improve T cell metabolism for improved anti-tumour function in these nutrient-depleted microenvironments.

scholarly journals Opa+ and Opa− Isolates of Neisseria meningitidis and Neisseria gonorrhoeae Induce Sustained Proliferative Responses in Human CD4+ T Cells

2009 ◽  
Vol 77 (11) ◽  
pp. 5170-5180 ◽  
Author(s):  
Abdel-Rahman Youssef ◽  
Michiel van der Flier ◽  
Silvia Estevão ◽  
Nico G. Hartwig ◽  
Peter van der Ley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neisseria Meningitidis ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Activated T Cells ◽  
Bacterial Surface ◽  
Host Immune Responses ◽  
Cell Functions

ABSTRACT T cells may interact with a number of bacterial surface antigens, an encounter which has the potential to downmodulate host immune responses. Neisseria meningitidis, a human colonizer and an agent of septicemia and meningitis, expresses Opa proteins which interact with the CEACAM1 receptor expressed on activated T cells. Since CEACAM1 can act as an inhibitory receptor and T cells in subepithelial tissues may encounter whole bacteria, which often express Opa proteins in vivo, this study assessed primarily if Opa proteins expressed on meningococci affect T-cell functions. In addition, Opa-containing outer membrane vesicles (OMV) have been used as vaccine antigens, and therefore Opa+ and Opa− OMV were also studied. While Opa+ bacteria adhered to CEACAM-expressing T cells, both the Opa+ and Opa− phenotypes induced no to a small transient depression, followed by a prolonged increase in proliferation as well as cytokine production. Such responses were also observed with heat-killed bacteria or OMV. In addition, while anti-CEACAM antibodies alone inhibited proliferation, on coincubation of T cells with bacteria and the antibodies, bacterial effects predominated and were Opa independent. Thus, while Opa proteins of N. meningitidis can bind to T-cell-expressed CEACAM1, this is not sufficient to overcome the T-cell recognition of bacterial factors, which results in a proliferative and cytokine response, an observation consistent with the ability of the host to establish lasting immunity to Opa-expressing meningococci that it frequently encounters. The data also imply that Opa-proficient vaccine preparations may not necessarily inhibit T-cell functions via CEACAM1 binding.

scholarly journals Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Teresa Manzo ◽  
Boone M. Prentice ◽  
Kristin G. Anderson ◽  
Ayush Raman ◽  
Aislyn Schalck ◽  
...  
Keyword(s):  
Fatty Acids ◽  
T Cells ◽  
Lipid Metabolism ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Metabolic Reprogramming ◽  
Long Chain Fatty Acids ◽  
Cell Functions ◽  
Long Chain ◽  
Chain Fatty Acids

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

Effect of Ivig On Human T Cells: Interference with Activation Rather Than Suppression of Activated Cell Functions.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4738-4738
Author(s):  
Lauriane Padet ◽  
Isabelle St-Amour ◽  
Eric Aubin ◽  
Real Lemieux ◽  
Renee Bazin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
In Vitro Assays ◽  
Activated T Cells ◽  
Cell Functions ◽  
Human T Cells

Abstract Abstract 4738 Introduction IVIg is known to have immunosuppressive effects in a variety of inflammatory and autoimmune diseases, which may be caused by modulations of T cell functions in treated patients. The mechanisms responsible for these modulations have been mostly investigated using in vitro stimulated T cells. These studies revealed that IVIg inhibited the proliferation of activated T cells possibly by interfering with the secretion of cytokines important for T cell proliferation, such as IL-2. In the present study, we sought to determine the precise mechanism by which IVIg inhibited cytokine secretion by stimulated T cells. Methods Human PBMC and Jurkat T cells were stimulated with PHA. Human T cells purified from PBMC were stimulated with CD3/CD28 T cell expander beads. Cells were cultured in presence or not of 10 mg/ml of IVIg for 24 hours. IL-2 secretion was measured in the culture supernatants by ELISA. IVIg was depleted of PHA-reactive IgG by passage on a PHA-Sepharose column. The extent of depletion was evaluated by ELISA using PHA as capture antigen. The role of F(ab')2 fragments in the inhibitory effect of IVIg on IL-2 secretion was determined using pepsin-generated fragments. Results IVIg inhibited IL-2 secretion by PHA-stimulated T cells, as previously reported. However, the use of increasing concentrations of PHA for T cell stimulation led to a decreased ability of IVIg to inhibit IL-2 production, suggesting that IVIg acted by neutralizing PHA or by competition for receptor occupancy on the cell surface. Pre-incubation of T cells with IVIg followed by washing and addition of PHA did not result in inhibition of IL-2 secretion, indicating that competition for receptor was not involved in this IVIg-mediated inhibition. In contrast, inhibition of IL-2 production by IVIg was completely abrogated using IVIg depleted from PHA-reactive IgG, indicating that IVIg-mediated inhibition of IL-2 secretion was the consequence PHA neutralization. Testing of F(ab')2 fragments of IVIg showed that these fragments bound to PHA and inhibited IL-2 secretion as efficiently as IVIg. Using another activation strategy, we showed that IVIg could also decrease IL-2 secretion by purified human T cells following anti-CD3/CD28 stimulation. Preliminary data using light microscopy indicated that IVIg interfered with the binding of CD3/CD28 beads on T cells, therefore reducing cell activation as evaluated by IL-2 secretion. Conclusion Altogether, our results suggest that the inhibition of T cell responses by IVIg occurs during the cell activation step, by preventing the binding of mitogens or antibody-coated beads on the cell surface. These observations emphasize the importance of ruling out the possible interactions of IVIg with culture medium additives, mitogens or activating agents before deriving strong conclusions on the mechanisms of action of IVIg based on their apparent immunomodulatory effects observed in vitro assays. Disclosures: No relevant conflicts of interest to declare.

Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells

Blood ◽  
2009 ◽  
Vol 113 (13) ◽  
pp. 2955-2964 ◽  
Author(s):  
Cristina Cerboni ◽  
Michele Ardolino ◽  
Angela Santoni ◽  
Alessandra Zingoni
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Cultures ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Γδ T Cells ◽  
Activated T Cells ◽  
Cell Functions ◽  
Major Player ◽  
Activating Receptor

Abstract NKG2D is an activating receptor expressed on CD8+αβ+ T cells, γδ+ T cells, natural killer (NK) cells, and some CD4+ T cells. For a long time, the interaction of NKG2D with its ligands (NKG2DLs) MICA, MICB, and ULBP1-3 has been considered a mechanism for recognition and elimination of tumor, infected, or otherwise “stressed” cells. However, a new role for NKG2D as an immunoregulatory receptor is emerging. Here, we show that NKG2D is strongly down-modulated on antigen-activated CD8+ T cells but only if CD4+ T cells are present. Down-modulation was caused by soluble factors produced by CD4+ T cells, and in particular soluble NKG2DLs were found in the supernatants of antigen-activated T-cell cultures. MICB was the ligand released at higher levels when CD4+ T cells were present in the cell cultures, suggesting that it could be the major player of NKG2D down-modulation. CD8+ T cells expressing low levels of NKG2D had impaired effector functions, as evaluated by proliferation, cytokine production, and cytotoxicity assays after combined triggering of NKG2D and TCR-CD3 complex. These findings show that activated CD4+ T cells expressing NKG2DLs can efficiently prevent NKG2D-mediated CD8+ T-cell functions, and suggest that the NKG2D/NKG2DL interaction can regulate immune responses.

scholarly journals RNA Flow Cytometry for the Study of T Cell Metabolism

2021 ◽  
Vol 22 (8) ◽  
pp. 3906
Author(s):  
Alessandra Rossi ◽  
Ilenia Pacella ◽  
Silvia Piconese
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Through Flow ◽  
Invaluable Tool ◽  
Epigenetic Remodeling ◽  
The One

T cells undergo activation and differentiation programs along a continuum of states that can be tracked through flow cytometry using a combination of surface and intracellular markers. Such dynamic behavior is the result of transcriptional and post-transcriptional events, initiated and sustained by the activation of specific transcription factors and by epigenetic remodeling. These signaling pathways are tightly integrated with metabolic routes in a bidirectional manner: on the one hand, T cell receptors and costimulatory molecules activate metabolic reprogramming; on the other hand, metabolites modify T cell transcriptional programs and functions. Flow cytometry represents an invaluable tool to analyze the integration of phenotypical, functional, metabolic and transcriptional features, at the single cell level in heterogeneous T cell populations, and from complex microenvironments, with potential clinical application in monitoring the efficacy of cancer immunotherapy. Here, we review the most recent advances in flow cytometry-based analysis of gene expression, in combination with indicators of mitochondrial activity, with the aim of revealing and characterizing major metabolic pathways in T cells.

scholarly journals Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Guillermo O. Rangel Rivera ◽  
Hannah M. Knochelmann ◽  
Connor J. Dwyer ◽  
Aubrey S. Smith ◽  
Megan M. Wyatt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Metabolic Pathways ◽  
Cell Activation ◽  
Cell Metabolism ◽  
Building Blocks ◽  
Cell Mediated Immunity ◽  
Cytotoxic Molecules ◽  
Checkpoint Receptors

Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.

scholarly journals Amino Acid Metabolism in Lupus

2021 ◽  
Vol 12 ◽  
Author(s):  
Michihito Kono ◽  
Nobuya Yoshida ◽  
George C. Tsokos
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Activation ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Cell Metabolism ◽  
Cell Subset ◽  
Metabolic Reprogramming ◽  
Acid Oxidation

T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.

scholarly journals Metabolic and functional impairment of CD8+ T cells from the lungs of influenza-infected obese mice

2020 ◽  
Author(s):  
William D. Green ◽  
Abrar E. Al-Shaer ◽  
Qing Shi ◽  
Nancie J MacIver ◽  
Melinda A. Beck ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Post Infection ◽  
Cytokine Production ◽  
Cell Metabolism ◽  
Metabolic Reprogramming ◽  
Obese Mice ◽  
Diet Induced Obesity ◽  
And Function

ABSTRACTBackgroundObesity increases influenza disease risk in millions of adults worldwide. In this study, we investigated the effect of diet-induced obesity on pulmonary CD8+ T cell metabolism and function as a mechanism of impairment.MethodsMale C57BL/6J mice were fed either control (10% kcal/g) or high-fat (60% kcal/g) diet. Sub-lethal A/PR/8/34 influenza virus infection generated a robust pulmonary immune response. T cell metabolism and function were assessed at day 10 and day 24 post infection.ResultsAt day 10 post infection, CD8+ T cells from obese mice had impaired oxidative and glycolytic metabolism, greater fatty acid uptake, and decreased effector populations and cytokine production. At infection resolution, obese mice had lower numbers of naïve and central memory CD8+ T cell populations in the lungs.ConclusionDiet-induced obesity increases influenza virus pathogenesis through CD8+ T cell mediated metabolic reprogramming resulting in suppressed effector CD8+ T cell function.SummaryDiet-induced obesity impairs the metabolism of pulmonary CD8+ T cells resulting in reduced effector CD8+ T cells and cytokine production following primary influenza infection.

Effect of STING agonist on tumor immune microenvironment of non-inflamed lung cancer and efficacy of immune checkpoint blockade.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 178-178
Author(s):  
Hongjae Chon
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Lung Carcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Anti Cancer

178 Background: Cancer immunotherapy targeting immune checkpoints are now emerging as a promising therapeutic strategy in various tumors. However, the treatment of T cell non-inflamed tumor which lacks intratumoral T cell infiltrates are still major clinical hurdle. Therefore, drugs that target signaling pathways to increase T cell infiltration in non-inflamed tumor microenvironment (TME) should be investigated. In this study, we aimed to explore the therapeutic potential of STING agonist in murine model of non-small cell lung cancer to overcome immunotherapy resistance. Methods: C57BL/6 mice, which are 6 to 8 weeks of age, were used for the experiment. Mice were injected with Lewis lung carcinoma cells on the right flank. STING agonist (cGAMP) was injected intratumorally. CD8+ and CD31+ cells were detected using immunofluorescence (IF) staining. Gene expressions of tumor microenvironment were analyzed by NanoString RNA sequencing. Flow cytometry (FACS) was performed to detect CD8+, CD4+, Treg and myeloid cell population. Tumor growths were evaluated in combination with anti-PD1 and STING agonist treatment. Results: Local injection of STING agonist effectively delayed tumor growth of LLC. STING agonist increased intratumoral CD8+ T cells and vascular disruption. Expressions of inhibitory checkpoint molecules (PD-1, PD-L1), cytokines (IFN), CD8+ and CD4+ T cells were increased, which showed that anti-cancer immune responses were augmented. Combination treatment of anti-PD-1 antibody and STING agonist synergistically decreased tumor growth. Conclusions: In this study, STING agonist was shown to delay tumor growth and remodel tumor microenvironment in non-inflamed lung carcinoma model. Combination therapy of STING agonist and immune checkpoint inhibitors (ICI) targeting PD-1 synergistically suppressed the growth of lung cancer which is resistant to ICI monotherapy. Collectively, our findings demonstrated that localized STING therapy effectively sensitizes non-inflamed lung cancer to systemic ICI treatment and induces a maximal anti-cancer immune response.

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