Cancer Cell-Intrinsic SSBP4 Enables Tumor Immune Evasion by Promoting Cholesterol Biosynthesis

Area of Science:

• Immunology
• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• The tumor microenvironment (TME) often suppresses anti-tumor immune responses, leading to resistance against immunotherapies like checkpoint inhibitors.
• Key factors driving the immunosuppressive TME and impacting immunotherapy efficacy remain incompletely understood.

Purpose of the Study:

• To identify novel cancer cell-intrinsic factors that regulate the tumor immune microenvironment.
• To elucidate the mechanism by which Single-Stranded DNA Binding Protein 4 (SSBP4) influences T-cell function and tumor growth.
• To evaluate SSBP4 as a potential therapeutic target for enhancing anti-cancer immunity and immunotherapy.

Main Methods:

• Utilized murine syngeneic tumor models to assess the effects of SSBP4 overexpression and genetic ablation on tumor growth and T-cell infiltration.
• Investigated the molecular mechanisms by which SSBP4 impacts cholesterol metabolism and T-cell activation.
• Assessed the efficacy of anti-PD-1 immunotherapy in conjunction with SSBP4 modulation.

Main Results:

• SSBP4 overexpression in tumor cells decreased intratumoral T-cell infiltration and accelerated tumor growth.
• Genetic ablation of SSBP4 enhanced T-cell infiltration and inhibited tumor growth in a CD8+ T cell-dependent manner.
• SSBP4 upregulates cholesterol synthesis, leading to increased cholesteryl ester production that directly suppresses CD8+ T-cell activation and function.
• SSBP4 abrogation significantly improved the efficacy of anti-PD-1 treatment.

Conclusions:

• SSBP4 is a novel cancer cell-intrinsic regulator of cholesterol metabolism that promotes tumor immune evasion.
• Targeting SSBP4-mediated cholesterol metabolism represents a potential strategy to overcome resistance to checkpoint inhibitors and enhance anti-tumor immunity.