Optical Control of CD8+ T Cell Metabolism and Effector Functions

Amitrano, Andrea M.; Berry, Brandon J.; Lim, Kihong; Kim, Kyun Do; Waugh, Richard E.; Wojtovich, Andrew P.; Kim, Min‐Soo

doi:10.3389/fimmu.2021.666231

Cited by 26 publications

(24 citation statements)

References 57 publications

(76 reference statements)

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“…Since the advent of optogenetics, many top medical journals have described it as a core technology for the future of humanity ( Method of the year, 2010 ; News, 2010 ; Adamantidis et al, 2015 ). Optogenetics can be combined with molecular biology, viral biology and other methods to introduce foreign light-sensitive protein genes into living cells ( Amitrano et al, 2021 ; Di Ventura and Weber, 2021 ). Therefore, optogenetics has made many achievements in the field of neurobiology.…”

Section: Introductionmentioning

confidence: 99%

The Roles of Optogenetics and Technology in Neurobiology: A Review

Chen

Liang

et al. 2022

Front. Aging Neurosci.

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Optogenetic is a technique that combines optics and genetics to control specific neurons. This technique usually uses adenoviruses that encode photosensitive protein. The adenovirus may concentrate in a specific neural region. By shining light on the target nerve region, the photosensitive protein encoded by the adenovirus is controlled. Photosensitive proteins controlled by light can selectively allow ions inside and outside the cell membrane to pass through, resulting in inhibition or activation effects. Due to the high precision and minimally invasive, optogenetics has achieved good results in many fields, especially in the field of neuron functions and neural circuits. Significant advances have also been made in the study of many clinical diseases. This review focuses on the research of optogenetics in the field of neurobiology. These include how to use optogenetics to control nerve cells, study neural circuits, and treat diseases by changing the state of neurons. We hoped that this review will give a comprehensive understanding of the progress of optogenetics in the field of neurobiology.

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Section: Introductionmentioning

confidence: 99%

The Roles of Optogenetics and Technology in Neurobiology: A Review

Chen

Liang

et al. 2022

Front. Aging Neurosci.

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“…Recent study showed that G6PD is essential for mitochondrial function 33 and mitochondrial metabolic pathway regulates Gzmb expression in T cells. 34 It is known that the PPP metabolic pathway enhances mitochondrial acetyl-CoA production. 35 Analysis of genome-wide H3K9ac ChIP-Seq dataset in human T cells identified H3K9ac deposition at the GZMB promoter ( figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes

Yang

Klement

et al. 2022

J Immunother Cancer

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BackgroundGranzyme B is a key effector of cytotoxic T lymphocytes (CTLs), and its expression level positively correlates with the response of patients with mesothelioma to immune checkpoint inhibitor immunotherapy. Whether metabolic pathways regulate Gzmb expression in CTLs is incompletely understood.MethodsA tumor-specific CTL and tumor coculture model and a tumor-bearing mouse model were used to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in CTL function and tumor immune evasion. A link between granzyme B expression and patient survival was analyzed in human patients with epithelioid mesothelioma.ResultsMesothelioma cells alone are sufficient to activate tumor-specific CTLs and to enhance aerobic glycolysis to induce a PD-1hi Gzmblo CTL phenotype. However, inhibition of lactate dehydrogenase A, the key enzyme of the aerobic glycolysis pathway, has no significant effect on tumor-induced CTL activation. Tumor cells induce H3K9me3 deposition at the promoter of G6pd, the gene that encodes the rate-limiting enzyme G6PD in the pentose phosphate pathway, to downregulate G6pd expression in tumor-specific CTLs. G6PD activation increases acetyl-coenzyme A (CoA) production to increase H3K9ac deposition at the Gzmb promoter and to increase Gzmb expression in tumor-specific CTLs converting them from a Gzmblo to a Gzmbhi phenotype, thus increasing CTL tumor lytic activity. Activation of G6PD increases Gzmb+ tumor-specific CTLs and suppresses tumor growth in tumor-bearing mice. Consistent with these findings, GZMB expression level was found to correlate with increased survival in patients with epithelioid mesothelioma.ConclusionG6PD is a metabolic checkpoint in tumor-activated CTLs. The H3K9me3/G6PD/acetyl-CoA/H3K9ac/Gzmb pathway is particularly important in CTL activation and immune evasion in epithelioid mesothelioma.

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“…Recently, Amitrano et al set up a novel optogenetic approach based on light stimulation to specifically and remotely control T-cell OXPHOS. The authors were able to increase mitochondrial efficiency and ATP production in T cells, this having a positive effect on effector functions, including in vitro migration [ 127 ]. However, the application of this strategy in cancer immunotherapy requires further studies.…”

Section: Restoring Defective Car T Cell Migration By Targeting Immune...mentioning

confidence: 99%

Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?

Simula

Ollivier

Icard

et al. 2022

Cells

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Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remission. In most solid tumors for which CAR T-cell therapy has been tested, efficacy has been very limited. In this context, it is of paramount importance to understand the mechanisms of tumor resistance to CAR T cells. Possible factors contributing to such resistance have been identified, including inherent CAR T-cell dysfunction, the presence of an immunosuppressive tumor microenvironment, and tumor-intrinsic factors. To control tumor growth, CAR T cells have to migrate actively enabling a productive conjugate with their targets. To date, many cells and factors contained within the tumor microenvironment have been reported to negatively control the migration of T cells and their ability to reach cancer cells. Recent evidence suggests that additional determinants, such as immune checkpoint proteins, cellular metabolism, and adhesion molecules, may modulate the motility of CAR T cells in tumors. Here, we review the potential impact of these determinants on CAR T-cell motility, and we discuss possible strategies to restore intratumoral T-cell migration with a special emphasis on approaches targeting these determinants.

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Optical Control of CD8+ T Cell Metabolism and Effector Functions

Cited by 26 publications

References 57 publications

The Roles of Optogenetics and Technology in Neurobiology: A Review

The Roles of Optogenetics and Technology in Neurobiology: A Review

G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes

Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?

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