2. Academic Validation
  3. Docosahexaenoic acid reverses PD-L1-mediated immune suppression by accelerating its ubiquitin-proteasome degradation

Docosahexaenoic acid reverses PD-L1-mediated immune suppression by accelerating its ubiquitin-proteasome degradation

  • J Nutr Biochem. 2022 Oct 26;109186. doi: 10.1016/j.jnutbio.2022.109186.
Han Zhang 1,  Hui Chen 1,  Shutao Yin 1,  Lihong Fan 2,  Caiwei Jin 3,  Chong Zhao 4,  Hongbo Hu 5
Affiliations

Affiliations

  • 1 College of Food Science and Nutritional Engineering, China Agricultural University, No 17, Qinghua East Road, Haidian District, Beijing, 10083, China.
  • 2 College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing, 100193, China.
  • 3 Department of Intensive Care Unit, People's Hospital of Luancheng District, Hebei Province, 051430, China.
  • 4 College of Food Science and Nutritional Engineering, China Agricultural University, No 17, Qinghua East Road, Haidian District, Beijing, 10083, China. Electronic address: zhaoch0206@cau.edu.cn.
  • 5 College of Food Science and Nutritional Engineering, China Agricultural University, No 17, Qinghua East Road, Haidian District, Beijing, 10083, China. Electronic address: hongbo@cau.edu.cn.
PMID: 36309154 DOI: 10.1016/j.jnutbio.2022.109186
Abstract

PD-L1 interacts with its receptor PD-1 on T cells to negatively regulate T cell function, leading to Cancer cell immune escape from the immune surveillance. Therefore, targeting PD-L1 is considered to be an attractive approach for Cancer Immunotherapy. In this study, we demonstrated for the first time that ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduced the expression of PD-L1 in Cancer cells both in vitro and in vivo. Promotion of PD-L1 ubiquitin-proteasome degradation by DHA resulted in a decrease of PD-L1 expression, leading to reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. Furtherly, DHA significantly reduced fatty acid synthase (FASN) expression in Cancer cells, which inhibited the palmitoyltransferases DHHC5, promoting the CSN5-dependent PD-L1 degradation. Our present finding uncovered a novel mechanism involved in the anti-cancer activity of DHA, and implicated that DHA holds promising potential to be developed as a novel immune-enhancer for Cancer treatment and prevention.

Keywords

PD-L1; docosahexaenoic acid; immune suppression; non-small cell lung cancer; ubiquitin-proteasome degradation.

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