DOI: 10.1161/atvbaha.126.324936 ISSN: 1079-5642

Impaired NK Cell–Mediated Tumor Surveillance in Atherosclerosis Due to Plaque-Induced PPARα Dysfunction

Tong Ren, Shengnan Yu, Xilin Jiang, Jing Wen, Changsheng Yan, Dan Du, Jian Tang, Lu Peng, Sangang Wu, Cuilian Dai, Enhui Yao, Xin Jin, Lichao Yang
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BACKGROUND:

Atherosclerosis is frequently associated with both an increased incidence and accelerated development of cancer. However, the impact of atherosclerosis progression on the efficacy of tumor surveillance by cytotoxic immune cells, particularly natural killer (NK) cells, remains poorly understood. This study aims to explore how atherosclerosis affects NK cell–mediated tumor surveillance in both animal models and humans.

METHODS:

We analyzed peripheral blood NK cells from patients with atherosclerosis with early-stage (<50% stenosis) versus advanced-stage (≥50% stenosis) coronary artery lesions by flow cytometry to assess NK cell frequency, PPARα (peroxisome proliferator–activated receptor alpha) expression, and IFN-γ (interferon gamma) production. In parallel, we used atherosclerotic plaque progression and regression models, including high-fat diet-fed Apo –/– mice and aortic arch transplantation into wild-type, Apoe –/– , Rag1 –/– , and NK cell–specific PPARα knockout ( Ppara flox/flox Ncr1 Cre/+ ) mice. NK cell phenotype and function were evaluated by flow cytometry for immune checkpoint molecules (PD-1 [programmed cell death protein-1], TIM-3 [T-cell immunoglobulin and mucin-domain containing-3], LAG-3 [lymphocyte activation gene-3], and TIGIT [T-cell immunoglobulin and ITIM domain]) and effector cytokines (IFN-γ, GZMB [granzyme B]). Antitumor capacity was assessed in B16F10 melanoma and ID8 ovarian cancer models in atherosclerosis mice, with or without a PPARα agonist (oleoylethanolamide) or an mTOR (mechanistic target of rapamycin kinase) agonist (MHY1485) treatment. Mechanistic studies included immunoblotting for mTOR pathway components and transcriptomic correlation analyses (GSE94044, GSE24495).

RESULTS:

We found that atherosclerotic plaques induced PPARα deficiency in NK cells, which impaired their cytotoxicity and weakened tumor immunosurveillance. Mechanistically, PPARα-deficient NK cells exhibited elevated immune checkpoint expression, an exhaustion phenotype, and markedly diminished mTOR signaling. Administration of the PPARα agonist oleoylethanolamide restored NK cell effector function and enhanced tumor-killing efficacy in vivo, whereas mTOR agonism partially rescued the defect caused by PPARα loss. These findings underscore the suppressive effects of arterial plaques on NK cell–mediated antitumor immunity and suggest PPARα compensation as a potential immunotherapeutic strategy.

CONCLUSIONS:

Our study unveils a novel association between atherosclerosis and the attenuation of NK cell antitumor immunity. Specifically, plaque-induced downregulation of PPARα in NK cells leads to uncontrolled immune checkpoint expression, causing NK cell exhaustion and diminished antitumor function. Pharmacological enhancement of PPARα signaling rejuvenated NK cell activity and reduced tumor growth in atherosclerosis. Therefore, targeting PPARα offers a promising therapeutic approach for cancer treatment and prevention in individuals with atherosclerosis.

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