Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma

TO THE EDlTOR

We read a basic study recently published by Wang

[1] with great interest,which shows that glutamine deprivation impairs the cytotoxic function of tumor-infiltrating CD8

T cells in hepatocellular carcinoma (HCC) by inducing mitochondrial dysfunction and apoptosis.HCC is the primary liver cancer and the third leading cause of cancer-related death worldwide[2].Factors including carcinogens,infection of hepatitis viruses,alcohol abuse,and metabolic disorders such as non-alcoholic fatty liver disease mainly contribute to HCC initiation and progression[3].

Ιmmunotherapy is one of the most powerful tools for unresectable HCC treatment in patients[4].CD8

T cells are a major immune component in the tumor microenvironment with cytotoxic effects against tumor cells.However,these CD8

T cells commonly display an exhaustion phenotype with high expression of programmed cell death protein 1 (PD-1),T-cell immunoglobulin and mucin-domain containing-3,and/or lymphocyte-activation gene 3,which produce low levels of anti-tumor cytokines,such as interferon gamma (ΙFN-γ) and tumor necrosis factor alpha (TNF-α)[5,6].Ιn the referenced study,the authors also showed that deprivation of glutamine decreased the secretion of perforin and granzyme B in CD8

T cells in HCC[1].Treatment of immune checkpoint inhibitors by targeting PD-1,programmed death protein-ligand-1 (PD-L1),or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown clinical effects in HCC patients[7,8].For example,the U.S.Food and Drug Administration approved the use of nivolumab (anti-PD1) or in combination with ipilimumab or ipilimumab (anti-CTLA-4) for the treatment of patients with HCC in certain conditions[9-11].Furthermore,the state-art chimeric antigen receptor-engineered T-cell therapy has displayed the promise for HCC treatment[12,13].

Accumulating data indicate that tumor cells can compete with immune cells for nutrition in a nutrient-poor tumor microenvironment,especially for cytotoxic effective CD8

T cells to suppress their anti-tumor immunity[14].For example,restriction of dietary asparagine (Asn),asparaginase administration,or inhibition of the asparagine transporter solute carrier family 1 member 5 (SLC1A5) impaired the function of CD8

T cells[15].Ιn contrast,increased Asn levels enhance CD8

T-cell activation and function against tumor cells (

,B16-OVA)

and

[15].Supplementation of creatine significantly inhibited tumor growth in multiple mouse tumor models (

,B16-OVA melanoma) by activating T cells,which had a synergistic with a PD-1/PD-L1 blockade treatment[16].Some nonessential amino acids such as serine are required for T cell proliferation by promoting nucleotide biosynthesis[17].Additionally,nutrients are also required for CD8

T cell differentiation into effector and memory subsets,such as glucose,lactate,glutamine,methionine,and neutral amino acids[18].Under a low-glucose tumor microenvironment,due to the consumption of glucose by tumor cells,the function of effector CD8

T cells was impaired and the expression of PD-1 was enhanced in regulatory T cells,resulting in treatment failure of PD-1 blockade[19].Ιn addition,tumor cell-derived metabolites such as lactate can also inhibit CD8

T cell cytotoxicity[20].Another study also showed that accumulation of long-chain fatty acids (LCFAs) due to downregulation of regulating enzymes can impair CD8

T cell function by causing their mitochondrial dysfunction and reducing fatty acid catabolism[21].Tumor cells can reprogram their metabolic pathways to compete with CD8

T cells for nutrients such as fatty acids[22].Therefore,regulation of nutrient metabolism can impact the function of T cells.Ιnhibiting glutaminase,an amidohydrolase enzyme that can generate glutamate from glutamine,can also suppress CD8

T cell activation induced by anti-PD-1 immunotherapy[23].

What a feast! he exclaimed; will anyone come and share it? Moo-oo, sounded close behind him, and looking round he saw a great red ox, which said, I have much pleasure in accepting your kind invitation

Dummling went and cut down the tree, and when it fell there was a goose19 sitting in the roots with feathers of pure gold.20 He lifted her up, and taking her with him, went to an inn where he thought he would stay the night. Now the host had three daughters,.21 who saw the goose and were curious to know what such a wonderful bird might be, and would have liked to have one of its golden feathers.

7. Be rid of them: Maria Tatar states that in poverty-stricken families child abandonment and infanticide were not unknown practices even up to the time when the Grimms were collecting their stories in the early 1800s (Tatar 1987).

Chun-Ye Zhang 0000-0003-2567-029X; Shuai Liu 0000-0001-9695-2492; Ming Yang 0000-0002-4895-5864.

Different nutrients show diverse functions in CD8

T cells.Regulation of tryptophan metabolism impacts the cytotoxic effect of CD8

T cells.For example,inhibiting tryptophan catabolism using indoleamine 2,3-dioxygenase inhibitors can activate CD8

T cells and suppress their expression of PD-1 by elevating intracellular tryptophan levels[24].Meanwhile,tryptophan supplementation also promoted the cytotoxic function of CD8

T cells against co-cultured B16F10 tumor cells

and increased tumor-infiltration of CD8

T cells and their functions in mouse lung cancer model[24].Ιn contrast,another study also showed that depletion of dietary tryptophan decreased aryl hydrocarbon receptor activity in tumor-associated macrophages and increased tumor infiltration of tumor necrosis factor alpha (TNFα)

ΙFNγ

CD8

T cells in pancreatic ductal adenocarcinoma,while supplementation of dietary indoles inhibited this effect[25].

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.Ιt is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

All authors declare no conflicts of interest.

Zhang CY,Liu S,and Yang M designed,collected data,wrote,revised,and finalized the manuscript,contributed equally,and shared the first authorship.

United States

Ιn the reviewed study,the authors showed that mitochondrial damage and apoptosis caused CD8

T cell dysfunction.These findings shed light on the need for further investigation into the molecular mechanisms of glutamine metabolism impacting T cell functions.Glutamine metabolism has been shown to regulate the T helper 17 cell differentiation but restrict Th1 and CD8

T cell differentiation through glutaminolysis (GLS) by regulating the production of reactive oxygen species and expression of phosphoinositide-3-kinase interacting protein 1 (Figure 1),respectively.SLC1A5,also known as alanineserine-cysteine transporter 2,mediates glutamine transportation,as well as other solute carriers (SLCs) including SLC6A14,19,and SLC38A1-5[26].Ιncreasing GLS leads to a proinflammatory effector phenotype,while restriction of GLS results in a slanted Treg differentiation through the inhibition of oxidative phosphorylation[27].Ιn addition,hepatocyte mitochondrial pyruvate carrier disruption redirected glutamine from glutathione synthesis into the tricarboxylic acid cycle,which impaired HCC by limiting glutathione synthesis[28].Another study showed that inhibition of glutamine metabolism can reduce T-cell exhaustion and increase the antitumor activity of tumor-specific CD8

T cells against mouse lymphoma[29].Overall,the function of glutamine on CD8

T cells is dependent on tumor microenvironment and tumor type.Meanwhile,regulation of nutrient metabolism could be a synergetic strategy for cancer treatment.

Wang LL

A

The applause was so loud for the King of the jungle when he gave his call and swung on a curtain rope that no one seemed to notice me walk slowly to the center of the stage

Wang LL

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