Cell Metabolism Coenzyme A promotes the antitumor effect of T cells

Article | My best friend, the old red hat, immunotherapy is one of the effective means to intervene in tumors.
There are two main methods: one is to use tumor-specific killer T cells, and the other is to use antibodies targeting immune checkpoints [ 1]
.

Of course, immunotherapy is not suitable for all patients, so improving the details of immunotherapy to enhance its therapeutic effect is one of the hotspots of current research [2]
.

Cellular metabolic processes affect all aspects of T cell function [3]
.

In immunotherapy, enhancing mitochondrial metabolism and oxidative phosphorylation (OXPHOS) of T cells can enhance their activity, thereby improving antitumor performance [4]
.

Known methods to enhance the level of mitochondrial oxidative phosphorylation in T cells include enhancing fatty acid oxidation [2], mitochondrial biosynthesis [5], mitochondrial fusion [6], etc.
In addition, targeting T cell costimulatory factors such as 4-1BB can improve Cell oxidation level, thereby enhancing its anti-tumor effect [7]
.

On December 7, 2021, Pamela S.
Ohashi's research group from the University of Toronto, Canada published an article entitled Coenzyme A fuels T cell antitumor immunity in Cell Metabolism, finding that the Coenzyme A metabolic pathway can induce oxidative phosphorylation and enhance T cells antitumor effect
.

The author's previous work determined that CD8+ effector T cells can be divided into three categories by means of metabolomics: one is the traditional Tc1 that secretes IFN-r, the other is Tc17 that secretes IL-17, and the third is Tc22 that secretes IL-22 [8, 9]
.

Compared with the other two subtypes, Tc22 has the best anti-tumor effect, but the anti-tumor function of Tc22 does not depend on IL-22
.

In order to study the anti-tumor mechanism of Tc22, the authors used fine metabolomics and mass spectrometry methods, and found that the metabolic profiles of these three cell subtypes were different, and the basal oxygen consumption rate (a marker of oxidative phosphorylation level) and oxygen consumption of Tc22 The rate/acidification rate (a marker of glycolysis level) ratio was higher than the other two subtypes
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Moreover, by analyzing cellular metabolic pathways, the authors found that Tc22 highly expressed pantothenate/CoA pathway-related components
.

This pathway refers to the synthesis of pantothenate (that is, vitamin B5) through a series of metabolic reactions, which ultimately lead to the production of coenzyme
A.

In Tc22, the levels of many intermediates of this pathway were significantly decreased, while the level of coenzyme A was significantly increased, indicating that a large amount of pantothenate was gradually synthesized into coenzyme A, and in addition, IL-22 was produced in this process
.

To determine whether the pantothenate/CoA intermediate or the end product CoA affected IL-22 production, mice were additionally given either coenzyme A or pantothenate
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The authors found that coenzyme A promoted IL-22 production at higher levels than pantothenate
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In addition, the metabolic profile of CD8+ T cells treated with coenzyme A changed, and the level of oxidative phosphorylation was significantly increased
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Next, the authors investigated the specific mechanism by which coenzyme A promotes IL-22 production
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The authors found that coenzyme A can alter a variety of metabolic signals.
Specifically, under the action of coenzyme A, a large amount of glucose-derived pyruvate in cells enters the mitochondria, increasing the synthesis level of acetyl-CoA, thereby increasing the level of oxidative phosphorylation
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In addition, the authors determined by knockout mice and other methods that the hypoxia-inducible factor HIF-1a and the aryl hydrocarbon receptor AhR downstream of oxidative phosphorylation can be activated by coenzyme A, thereby inducing the production of IL-22
.

Finally, the authors investigated whether coenzyme A could promote its antitumor function by increasing the level of Tc22 activation
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The authors found that coenzyme A-treated T cells transfused back into mice had significantly lower tumor growth rates than untreated T cells transfused
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For mice that had already formed tumors, the tumors were significantly controlled after infusion of coenzyme A-treated CD8+ T cells
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These results all indicate that coenzyme A can significantly enhance the anti-tumor function of T cells
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In summary, the authors found that the CD8+ T cell subtype Tc22 has stronger anti-tumor ability, higher levels of pantothenate/CoA pathway, and higher required oxidative phosphorylation levels than other subtypes.

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Coenzyme A can enhance the oxidative phosphorylation level of T cells through HIF-1a and AhR
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In addition, in mouse tumor models, coenzyme A can significantly enhance the anti-tumor ability of T cells
.

Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
11.
010 Publisher: Eleven References [1] Waldman, AD, Fritz, JM, and Lenardo, MJ (2020).
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Instructions for reprinting [Original article] BioArt original articles are welcome to forward and share, and reprinting is prohibited without permission.
The copyright of all published works is owned by BioArt, Lien, SC, Han, S.
, Sayad, A.
, Mulder, DT, Garcia-Batres, CR, Elford, AR, Israni-Winger, K.
, Robert-Tissot, C.
, et al.
(2020).
IL6 induces an IL22+ CD8+ T-cell subset with potent antitumor function.
Cancer Immunol.
Res.
8, 321–333.
Instructions for reprinting【Original article】BioArt original article, you are welcome to forward and share it.
The copyright of the work is owned by BioArt, Lien, SC, Han, S.
, Sayad, A.
, Mulder, DT, Garcia-Batres, CR, Elford, AR, Israni-Winger, K.
, Robert-Tissot, C.
, et al.
(2020).
IL6 induces an IL22+ CD8+ T-cell subset with potent antitumor function.
Cancer Immunol.
Res.
8, 321–333.
Instructions for reprinting【Original article】BioArt original article, you are welcome to forward and share it.
The copyright of the work is owned by BioArt
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