Inhibition of RBPJ transcription complex promotes IL-17 and IFN-γ secretion by CD4⁺ T cells in hepatocellular...

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Hepatocellular carcinoma (HCC) exhibits an immunosuppressive tumor microenvironment (TME).
• Traditional therapies like gamma-secretase inhibitors (GSIs) for Notch signaling in HCC immunotherapy have limitations, including side effects due to lack of substrate specificity.
• RBPJ inhibitor-1 (RIN1), a novel small molecule, selectively inhibits RBPJ-NICD interaction and has shown efficacy in reducing CD8+ T cell exhaustion in HCC.

Purpose of the Study:

• To investigate the impact of RIN1 on CD4+ T cells in the context of HCC.
• To elucidate the mechanisms by which RIN1 modulates T cell responses and antitumor immunity.
• To evaluate the therapeutic potential of RIN1 as an immunostimulatory agent for HCC.

Main Methods:

• In vitro analysis of T cell cytokine secretion (IL-17, IFN-γ) and differentiation.
• Assessment of protein levels (STAT3, STAT4, TBX21) and transcription factor binding to gene promoters (IL-17, IFNG).
• In vivo studies in HCC models to evaluate T cell responses, tumor growth inhibition, and effects on regulatory T cells (Tregs) and PD-1 expression.

Main Results:

• RIN1 promoted IL-17 and IFN-γ secretion and Th17.1 differentiation in T cells.
• RIN1 upregulated STAT3, STAT4, and TBX21, enhancing transcription factor binding to IL-17 and IFNG promoters.
• In vivo, RIN1 boosted CD4+ T cell antitumor immunity, suppressed PD-1, reduced Tregs, and inhibited tumor growth, with IL-17R knockdown partially reversing these effects.

Conclusions:

• RIN1 enhances CD4+ T cell-mediated antitumor immunity in HCC through modulation of gene transcription and T cell subset differentiation.
• RIN1 demonstrates potential as an immunostimulatory agent for HCC immunotherapy.
• Targeting RBPJ-NICD interaction with RIN1 offers a promising strategy for overcoming HCC's immunosuppressive TME.