5-羟色胺受体5-HT2A作为HCC免疫治疗的潜在靶点

While recent clinical trials of combination immunotherapies for hepatocellular carcinoma (HCC) have shown promising clinical efficacy and survival improvements breakthroughs, there is still much room for further improvement. A key limiting factor for HCC immunotherapy is the intrinsic immunosuppression within the liver microenvironment, resulting in suboptimal priming of tumour-specific CD8 cytotoxic T cells and thus immune evasion by the tumour. Hence, identifying new key molecular pathways suppressing T cell responses within the liver is critical for the rational design of more effective combination immunotherapies for HCC. Here, we present evidence that targeting 5-HT2A serotonin receptor signalling could be a viable approach for HCC immunotherapy. Disruption of 5-HT2A signalling using either a selective antagonist small molecule, ketanserin, or by knockout of its coding gene Htr2a, augments the cytotoxic effector phenotype of mouse CD8 T cells activated in vitro with immunosuppressive liver NPCs. Similarly, abrogating 5-HT2A signalling in in vitro activated primary human CD8 T cells with ketanserin treatment or CRISPR-mediated disruption of the HTR2A gene also increased expression of the cytotoxic effector molecules Granzyme B and perforin. RNA-seq analysis of 5-HT2A signalling-deficient activated mouse CD8 T cells revealed increased expression of cytotoxicity-related genes such as Granzyme B and reduced expression of transcription factors downstream of MAP kinase signalling pathways. Consistent with these observations, 5-HT2A activation in CD8 T cells rapidly triggered phosphorylation of the p38, ERK, and JNK/SAP MAP kinases. In vivo, systemic ketanserin treatment significantly prolonged survival of HCC tumour-bearing mice and was non-inferior to alphaPDL1 + alphaVEGFA combination antibody treatment. Combining ketanserin with alphaPDL1 + alphaVEGFA antibodies also significantly prolonged survival relative to control-treated mice while preserving the occurrence of complete tumour regression observed with alphaPDL1 + alphaVEGFA treatment alone. Together, our data describe a role for 5-HT2A as a negative regulator of the cytotoxic effector phenotype in CD8 T cells and highlight the therapeutic potential of targeting 5-HT2A for HCC immunotherapy.