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Targeted inhibition of RBPJ transcription complex alleviates the exhaustion of CD8+ T cells in hepatocellular carcinoma

Impaired function of CD8+ T cells in hepatocellular carcinoma (HCC) is an important reason for acquired resistance. Compared with single-target inhibitors, small-molecule compounds that could both inhibit tumor cells and alleviate T cell exhaustion are more promising to reduce resistance. In this study, we screened immunosuppressive targets in HCC by combining cancer-immunity cycle score with weighted gene co-expression network and system analysis. Through in vitro and in vivo validation experiments, we found that one of the screened molecules, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), was negatively correlated with CD8+ T cell mediated killing function. More importantly, its transcription complex inhibitor RIN1 not only inhibited the malignant biological behaviors of HCC cells by inhibiting mTOR pathway, but also reduced the expression of PD-L1 and L-kynurenine synthesis in HCC cells, thus alleviating T cell exhaustion. Meanwhile, the combination of RIN1 and anti-PD-1/PD-L1 antibodies could further activate CD8+ T cells. In short, RBPJ is an important factor regulating the function of T cells. Target inhibition of RBPJ transcription complex by small molecule compound may be a new strategy for immunotherapy of HCC.

 

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This study suggests that impaired function of CD8+ T cells in hepatocellular carcinoma (HCC) is a major contributor to acquired resistance, and small-molecule compounds that inhibit tumor cells while alleviating T cell exhaustion may be a promising strategy to reduce resistance. The researchers used a combination of cancer-immunity cycle score, weighted gene co-expression network, and system analysis to screen for immunosuppressive targets in HCC. They found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) was negatively correlated with CD8+ T cell mediated killing function.

Through in vitro and in vivo experiments, the researchers validated that RIN1, a transcription complex inhibitor of RBPJ, not only inhibited the malignant behaviors of HCC cells by inhibiting the mTOR pathway but also reduced the expression of PD-L1 and L-kynurenine synthesis in HCC cells, thereby alleviating T cell exhaustion. Additionally, the combination of RIN1 and anti-PD-1/PD-L1 antibodies further activated CD8+ T cells.

In conclusion, RBPJ is an important factor regulating T cell function, and targeting the RBPJ transcription complex with small molecule compounds may be a new strategy for immunotherapy of HCC.

Related Products

Cat.No. Product Name Information
S3376 RIN1 (RBPJ Inhibitor-1) RIN1 (RBPJ Inhibitor-1) is a potent inhibitor of the transcription factor RBPJ that disrupts the interaction between NOTCH and RBPJ.

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Notch