Pan-cancer immunogenomics and structure-guided repurposing identify N-Acetyl-L-carnosine as a PAR2 binding modulator

Area of Science:

• Oncology
• Immunology
• Pharmacology
• G protein-coupled receptor (GPCR) research

Background:

• The role of Protease Activated Receptor 2 (PAR2/F2RL1) in the tumor immune microenvironment is not well understood.
• PAR2 is a GPCR activated by proteolytic cleavage.
• Understanding PAR2's function is crucial for developing novel cancer immunotherapies.

Purpose of the Study:

• To investigate the role of PAR2 in shaping the tumor immune microenvironment across various cancer types.
• To identify potential therapeutic strategies targeting PAR2, particularly in cancers with high PAR2 expression.
• To discover novel small molecules that bind to PAR2.

Main Methods:

• Integrated immunogenomic analysis of 33 cancer types.
• Structure-based virtual screening of 5,954 compounds.
• Molecular docking, molecular dynamics simulations, MTT assays, and wound-healing assays.

Main Results:

• PAR2 was significantly upregulated in eight tumor types, notably head and neck squamous cell carcinoma (HNSC) and lung adenocarcinoma (LUAD).
• HNSC and LUAD exhibited immunosuppressive signatures and poor prognosis linked to PAR2 overexpression.
• N-Acetyl-L-carnosine (NAC), an antioxidant, was identified as an orthosteric PAR2 binder with stable and favorable binding, showing no toxicity and acting as a context-dependent modulator rather than an inhibitor.

Conclusions:

• PAR2 is a promising immunotherapeutic target for HNSC and LUAD, associated with immune suppression.
• N-Acetyl-L-carnosine (NAC) is a novel PAR2-binding molecule with potential therapeutic applications.
• Further validation of NAC's functional impact on PAR2 signaling through direct receptor-signaling assays is warranted.