Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

Wang, Tingting; Gnanaprakasam, JN Rashida; Chen, Xuyong; Kang, Siwen; Xu, Xuequn; Sun, Hua; Liu, Lingling; Rodgers, Hayley; Miller, Ethan; Cassel, Teresa; Sun, Qiong; Vicente-Muñoz, Sara; Warmoes, Marc O.; Lin, Penghui; Piedra-Quintero, Zayda L.; Guerau-de-Arellano, Mireia; Cassady, Kevin A.; Zheng, Song Guo; Yang, Jun J.; Lane, Andrew N.; Song, Xin; Fan, Teresa W.‐M.; Wang, Ruoning

doi:10.1038/s42255-020-0219-4

Cited by 165 publications

(106 citation statements)

References 82 publications

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“…Adenosine metabolites are unlikely to be mediating the suppression as enzyme supplementation with adenosine deaminase (ADA) restored recall and treatment with adenosine breakdown metabolite inosine (at equivalent concentrations) did not show any suppressive effect and in fact slightly increased recall (Fig. S3) consistent with recent evidence that CD8 + T cells can use inosine as an alternative carbon source to fuel expansion 14 . Coinhibitory receptor surface expression of PD-1 and LAG-3 is not significantly altered on day 7 tetramer positive T cells due to adenosine, whereas TIM-3 is downregulated.…”

Section: Resultssupporting

confidence: 80%

Antigen-Specific T Cell Recall Assay To Screen Drugs For Off-Target Effects

Kleiman

Sierra

Magcase

et al. 2020

Preprint

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Extracellular adenosine suppresses T cell immunity in the tumor microenvironment. We have developed an in vitro recall assay utilizing a sequential adenosine dosing regimen guide for testing drug off-target effects on memory T cell expansion/function. As a proof of principle, we show low dose adenosine analog GS-5734 does not alter memory T cell recall whereas toxicity observed at high dose favors antigen-specific memory T cell survival/proliferation over non-specific CD8+ T cells. Parent drug GS-445124 at high dosage interferes with antigen-specific T cell recall without cellular toxicity. Despite similar chemical structure, these drugs displayed opposing effects on memory T cell expansion. This assay platform has broad utility in screening memory T cell off-target effects.

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Section: Resultssupporting

confidence: 80%

Antigen-Specific T Cell Recall Assay To Screen Drugs For Off-Target Effects

Kleiman

Sierra

Magcase

et al. 2020

Preprint

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“…This immune-stimulatory effect though was context dependent, as it required co-stimulation in the form of exogenous IFN-g as well as IL-12 binding on T cells (151). Another recent study elucidated the role of inosine as an alternative carbon source for T cell metabolism in a glucose restricted setting, thereby assisting proliferation and differentiation of T cells and improving response to ICB, supporting the idea that inosine metabolism could be playing an integral part in anti-tumor immunity (160). These are intriguing findings when juxtaposed with the fledgling field of adenosine receptor (A 2A R) blockade for improving cancer immunotherapy (161,162) and indicate that the gut microbiome might influence how this therapy evolves.…”

Section: Inosine and Its Metabolitesmentioning

confidence: 90%

New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries

et al. 2021

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The past decade has witnessed groundbreaking advances in the field of microbiome research. An area where immense implications of the microbiome have been demonstrated is tumor biology. The microbiome affects tumor initiation and progression through direct effects on the tumor cells and indirectly through manipulation of the immune system. It can also determine response to cancer therapies and predict disease progression and survival. Modulation of the microbiome can be harnessed to potentiate the efficacy of immunotherapies and decrease their toxicity. In this review, we comprehensively dissect recent evidence regarding the interaction of the microbiome and anti-tumor immune machinery and outline the critical questions which need to be addressed as we further explore this dynamic colloquy.

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“…Although there may be recent findings that suggest inhibiting glutamine metabolism in the tumor may benefit T cells while impairing tumor metabolism (58). Often this tug of war forces effector T cells to use alternative carbon sources to survive (59)(60)(61). It is now clear that T cells use glycolysis to sustain their inflammatory potential, not only as a means to an end, but also as a regulatory component in T cell immunity.…”

Section: Glycolysis In Effector T Cell Functionmentioning

confidence: 99%

Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

et al. 2021

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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.

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Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

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Cited by 165 publications

References 82 publications

Antigen-Specific T Cell Recall Assay To Screen Drugs For Off-Target Effects

Antigen-Specific T Cell Recall Assay To Screen Drugs For Off-Target Effects

New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries

Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

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