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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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.
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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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DOI: https://doi.org/10.1007/s00262-023-03547-8