Serotonin receptor 5-HT_2A as a potential target for HCC immunotherapy

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Hepatocellular carcinoma (HCC) immunotherapy shows promise but requires improvement due to liver's immunosuppressive microenvironment.
• Identifying molecular pathways that suppress T cell responses is crucial for enhancing HCC immunotherapy efficacy.

Purpose of the Study:

• To identify novel molecular targets for HCC immunotherapy.
• To investigate the role of the 5-HT2A serotonin receptor in regulating T cell responses within the liver microenvironment.

Main Methods:

• Chemical screening identified 5-HT2A serotonin receptor as a potential target.
• In vitro and in vivo studies utilized ketanserin (5-HT2A antagonist) and gene knockout (Htr2a) to assess its impact on T cells.
• Combination therapy studies included ketanserin with anti-PD-L1 and anti-VEGFA antibodies.

Main Results:

• Disrupting 5-HT2A signaling augmented the cytotoxic effector phenotype of mouse and human CD8 T cells.
• Ketanserin treatment increased cytotoxic effector molecules (granzyme B, perforin) and related gene expression.
• In vivo, ketanserin prolonged survival in HCC-bearing mice, showing non-inferiority to existing combination therapies and enhancing their efficacy.

Conclusions:

• 5-HT2A serotonin receptor acts as a negative regulator of CD8 T cell cytotoxic function.
• Targeting 5-HT2A represents a promising therapeutic strategy for improving HCC immunotherapy.