2. Academic Validation
  3. Lipid accumulation-mediated histone hypoacetylation drives persistent NK cell dysfunction in anti-tumor immunity

Lipid accumulation-mediated histone hypoacetylation drives persistent NK cell dysfunction in anti-tumor immunity

  • Cell Rep. 2023 Oct 3;42(10):113211. doi: 10.1016/j.celrep.2023.113211.
Deyan Jiao 1,  Renhui Sun 1,  Xiaolei Ren 1,  Yingchun Wang 1,  Panpan Tian 1,  Yuzhen Wang 1,  Detian Yuan 2,  Xuetian Yue 3,  Zhuanchang Wu 4,  Chunyang Li 5,  Lifen Gao 4,  Chunhong Ma 6,  Xiaohong Liang 7
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China.
  • 3 Key Laboratory for Experimental Teratology of Ministry of Education and Department of Cell Biology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 4 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China; Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, Shandong, China.
  • 5 Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, China.
  • 6 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China; Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, Shandong, China. Electronic address: machunhong@sdu.edu.cn.
  • 7 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China; Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, Shandong, China. Electronic address: liangxiaohong@sdu.edu.cn.
PMID: 37792534 DOI: 10.1016/j.celrep.2023.113211
Abstract

Hyperlipidemia impairs anti-tumor immune responses and is closely associated with increased human Cancer incidence and mortality. However, the underlying mechanisms are not well understood. In the present study, we show that natural killer (NK) cells isolated from high-fat-diet mice or treated with oleic acid (OA) in vitro exhibit sustainable functional defects even after removal from hyperlipidemic milieu. This is accompanied by reduced chromatin accessibility in the promoter region of NK cell effector molecules. Mechanistically, OA exposure blunts P300-mediated c-Myc acetylation and shortens its protein half-life in NK cells, which in turn reduces P300 accumulation and H3K27 acetylation and leads to persistent NK cell dysfunction. NK cells engineered with hyperacetylated c-Myc mutants surmount the suppressive effect of hyperlipidemia and display superior anti-tumor activity. Our findings reveal the persistent dysfunction of NK cells in dyslipidemia milieu and extend engineered NK cells as a promising strategy for tumor immunotherapy.

Keywords

CP: Cancer; CP: Immunology; NK cell; c-Myc; histone acetylation; hyperlipidemia; persistent dysfunction.

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