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Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell

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Abstract

Increased prevalence of cancer in obese individuals is involved with dyslipidemia- induced chronic inflammation and immune suppression. Although apolipoprotein C-III (ApoC3)-transgenic mice (ApoC3TG mice) or poloxamer 407 (P407)-treated mice had hyperlipidemia, CD8+ T cells with upregulated antitumor activities were observed in ApoC3TG mice, and decreased CD8+ T cell activities were observed in P407-treated mice. Increased ApoC3 expression in hepatocellular carcinoma was associated with increased infiltration of CD8+ T cells and predicted survival. Recombinant ApoC3 had no direct effects on CD8+ T cells. The upregulation of CD8+ T cells in ApoC3TG mice was due to cross-talk with context cells, as indicated by metabolic changes and RNA sequencing results. In contrast to dendritic cells, the macrophages of ApoC3TG mice (macrophagesTG) displayed an activated phenotype and increased IL-1β, TNF-α, and IL-6 production. Coculture with macrophagesTG increased CD8+ T cell function, and the adoptive transfer of macrophagesTG suppressed tumor progression in vivo. Furthermore, spleen tyrosine kinase (Syk) activation induced by TLR2/TLR4 cross-linking after ApoC3 ligation promoted cellular phospholipase A2 (cPLA2) activation, which in turn activated NADPH oxidase 2 (NOX2) to promote an alternative mode of inflammasome activation. Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophagesTG. Collectively, the increased antitumor activity of CD8+ T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ApoC3:

Apolipoprotein C-III

Syk:

Spleen tyrosine kinase

cPLA2:

Cellular phospholipase A2

sPLA2:

Secreted PLA2

P407:

Poloxamer 407

HCC:

Hepatocellular carcinoma

IL-1β:

Interleukin-1β

TNF-α:

Tumor necrosis factor α

IL-6:

Interleukin-6

TLR2:

Toll-like receptor 2

TLR4:

Toll-like receptor 4

NADPH:

Nicotinamide adenine dinucleotide phosphate

ROS:

Reactive oxygen species

cROS:

Cytoplasmic ROS

mROS:

Mitochondrial ROS

MetSs:

Metabolic syndromes

VLDL:

Very-low-density lipoprotein

HDL:

High-density lipoprotein

HTG:

Hypertriglyceridemia

DCs:

Dendritic cells

ApoC3TG :

ApoC3-transgenic

CD36−/− :

CD36 knockout

IHC:

Immunohistochemical

AJCC:

American joint committee on cancer

ATCC:

American tissue culture collection

CPT1α:

Carnitine palmitoyltransferase 1α

SREBP1/2:

Sterol regulatory element binding protein 1/2

CGI58:

Comparative gene identification-58

ATGL:

Adipose triglyceride lipase

PD-L1:

Programmed death-ligand 1

NKG2D:

Natural killer group 2D

KLRG1:

Killer-cell lectin like receptor G1

IFN-γ:

Interferon-γ

IL-10:

Interleukin-10

TGF-β:

Transforming growth factor-β

GlUT1:

Glucose receptor

HK II:

Hexokinase II

ACC1:

Acetyl-CoA carboxylase 1

p-ACC1:

Phospho-ACC1

mTOR:

Mammalian target of rapamycin

mTORC1:

MTOR complex 1

LKB1:

Liver kinase B1

AMPK:

AMP kinase

Akt:

Protein kinase B

PPARγ:

Peroxisome proliferators-activated receptor γ

FOXO1:

Forkhead box protein O1

NLRP3:

NOD-like receptor family pyrin domain containing 3

Cas1:

Caspase 1, cysteinyl aspartate specific proteinase 1

Cas8:

Cysteinyl aspartate specific proteinase 8

c-Cas1:

Cleaved caspase 1

c-Cac8:

Cleaved caspase 8

RIPK1:

Receptor-interacting protein kinase 1

GSDMD:

Gasdermin D

PI3K p110α:

Phosphatidylinositol 3-kinase p110α

NF-κB:

Nuclear transcription factor-κB

NOX2:

NADPH oxidase

CCDC109A:

Coiled-coil domain containing 109A

FITC:

Fluorescein isothiocyanate

PI:

Propidium iodide

CFSE:

5,6-Carboxyfluorescein diacetate, succinimidyl ester

DCFH-DA:

2,7-Dichlorodihydrofluorescein diacetate

PVDF:

Polyvinylidene fluoride

ECAR:

Extracellular acidification rate

OCR:

Oxygen consumption rate

LPS:

Lipopolysaccharide

LDH:

Lactate dehydrogenase

ANOVA:

Analysis of variance

FFAs:

Free fatty acids

TCGA:

The cancer genome atlas

TME:

Tumor microenvironment

OVA:

Ovalbumin

WT:

Wild type

PA:

Palmitic acid

NAC:

N-acetyl-L-cysteine

TRPM2:

Transient receptor potential cation channel

FA:

Flufenamic acid

FAO:

Fatty acid oxidation

DEGs:

Differentially expressed genes

KEGG:

KYOTO encyclopedia of genes and genomes

HY:

Hybrid mice, ApoC3TG-CD36± mice

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Acknowledgements

We are grateful to Prof. George Liu and Prof. Qiang You for providing ApoC3TG mice and CD36−/− mice respectively.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81873867, 81671547, and 81873866), the Natural Science Foundation of Jiangsu Province, China (Grant Nos. BK20161339, and BK20160479); the “Six peaks” Talent Project of Jiangsu Province.

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Author notes

  1. Co-first authors: Xiangyu Hu and Shizhen Ding.

Authors and Affiliations

  1. Department of Basic Medicine, School of Medicine, Yangzhou University, Yangzhou, 225001, People’s Republic of China

    Xiangyu Hu, Shizhen Ding, Zhijie Lin, Liting Liao, Weijuan Gong & Xiaoqin Jia

  2. Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225001, People’s Republic of China

    Guotao Lu, Weiming Xiao, Yanbing Ding & Weijuan Gong

  3. School of Nursing, Yangzhou University, Yangzhou, 225001, People’s Republic of China

    Yu Zhang

  4. Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225001, People’s Republic of China

    Zhengbing Wang

  5. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, 225001, People’s Republic of China

    Weijuan Gong

  6. Jiangsu Key Laboratory of Zoonosis, Yangzhou, 225001, People’s Republic of China

    Yu Zhang & Weijuan Gong

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Contributions

XJ conceived the study. WG, GL, XH, XJ and ZW designed the experiments. XH, ZL, LL, and SD conducted the experiments. WX, YD, and YZ collected biopsies of HCC. WG, GL, XH and XJ analyzed the data and wrote the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Xiaoqin Jia.

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There are no financial conflicts of interest with regard to this work.

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of the Affiliated Hospital of Yangzhou University and obtained informed consent from all the patients. All animal protocols were approved by the Institutional Animal Care and Use Committee of Yangzhou University.

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Hu, X., Ding, S., Lu, G. et al. Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell. Cancer Immunol Immunother 72, 4123–4144 (2023). https://doi.org/10.1007/s00262-023-03547-8

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