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

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Programmed death-ligand 1 (PD-L1) interacts with its receptor PD-1 on T cells, inhibiting anti-tumor immunity and promoting cancer immune escape.
• Targeting the PD-L1 pathway is a key strategy in cancer immunotherapy.

Purpose of the Study:

• To investigate the effect of docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), on PD-L1 expression in cancer cells.
• To elucidate the underlying mechanism of DHA's action on PD-L1 and its impact on anti-tumor immunity.

Main Methods:

• In vitro and in vivo experiments were conducted to assess DHA's impact on PD-L1 expression.
• Mechanistic studies involved analyzing PD-L1 ubiquitination-proteasome degradation pathways, fatty acid synthase (FASN) expression, and interactions with DHHC5 and CSN5.

Main Results:

• DHA significantly reduced PD-L1 expression in cancer cells both in vitro and in vivo.
• DHA promoted the ubiquitin-proteasome degradation of PD-L1, leading to decreased PD-L1/PD-1 interactions and reversed immune suppression.
• DHA inhibited fatty acid synthase (FASN) expression, which in turn promoted CSN5-dependent PD-L1 degradation.

Conclusions:

• DHA effectively reduces PD-L1 expression through enhanced degradation, thereby reversing immune suppression and inhibiting tumor growth.
• DHA uncovers a novel mechanism for its anti-cancer activity by modulating the FASN-DHHC5-CSN5 axis, highlighting its potential as an immune-enhancer for cancer treatment and prevention.