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GFRAL-Fc disarms GDF15 to reprogram tumor immunity and amplify PD-1 efficacy in hepatocellular carcinoma
Gege Shi1, Wangqian Zhang1, Fei Xie1
1State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'An, China.
Background:
Checkpoint inhibitors have revolutionized hepatocellular carcinoma (HCC) treatment, yet their efficacy remains limited in advanced stages, with suboptimal objective response rates. Growth differentiation factor 15 (GDF15), a dual-functional cytokine implicated in tumor progression and immunosuppression, represents a promising therapeutic target. This study aims to develop a novel GDF15-targeted strategy to improve HCC management and synergize with PD-1 blockade.
Methods:
GFRAL-Fc fusion proteins were generated by fusing the extracellular domain of GFRAL with IgG1 Fc. The anti-tumor efficacy and the anti-cachexia ability of GFRAL-Fc was evaluated in a spontaneous HCC model on GDF15 humanized mice. Additionally, the half-life and drug safety were evaluated in mice. To investigate the underlying mechanisms, a CyTOF analysis was utilized to analysis the immunoregulation effects of GFRAL-Fc within HCC. Finally, the anti-tumor effects of GFRAL-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed.
Results:
GFRAL-Fc targets GDF15 to simultaneously prevent GDF15-CD48 interaction-driven ERK activation and block GDF15-GFRAL binding. Treatment with GFRAL-Fc achieved dual antitumor effects: reducing tumor progression and attenuating cancer-associated cachexia. Combination with PD-1 blockade further enhanced antitumor efficacy, resulting in a substantial decrease in tumor nodules. Mechanistic studies revealed that GFRAL-Fc reprograms the immunosuppressive tumor microenvironment by suppressing Treg activation while enhancing CD8+ T cell cytotoxicity.
Conclusions:
Our findings validate GDF15 targeting as a viable strategy to overcome checkpoint inhibitor resistance in HCC. The GFRAL-Fc fusion protein demonstrates multimodal therapeutic benefits through metabolic regulation and immune remodeling, providing a clinically translatable approach to optimize PD-1-based regimens. This study addresses critical gaps in current HCC management and warrants further clinical validation.
Insights
A novel GFRAL-Fc fusion protein targets Growth Differentiation Factor 15 (GDF15) to improve hepatocellular carcinoma (HCC) treatment. This therapy enhances PD-1 blockade efficacy by reducing tumor progression and immune suppression.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Checkpoint inhibitors have advanced hepatocellular carcinoma (HCC) treatment but show limited efficacy in advanced stages.
- Growth Differentiation Factor 15 (GDF15) is a cytokine involved in tumor progression and immune suppression, presenting a therapeutic target.
- There is a need for strategies to enhance HCC treatment and overcome resistance to existing therapies.
Purpose of the Study:
- To develop a novel GDF15-targeted strategy for improved HCC management.
- To evaluate the synergistic effects of this strategy with PD-1 blockade.
- To investigate the underlying mechanisms of action.
Main Methods:
- Generation of GFRAL-Fc fusion proteins targeting GDF15.
- Assessment of anti-tumor and anti-cachexia efficacy in a spontaneous HCC model in GDF15 humanized mice.
- Evaluation of pharmacokinetics and safety.
- CyTOF analysis to elucidate immunoregulatory effects.
- Combination therapy studies with PD-1 inhibitors.
Main Results:
- GFRAL-Fc effectively targets GDF15, inhibiting tumor progression and cachexia.
- Combination therapy with PD-1 blockade significantly enhanced anti-tumor efficacy, reducing tumor nodules.
- GFRAL-Fc reprogrammed the tumor microenvironment by suppressing regulatory T cells (Tregs) and boosting CD8+ T cell activity.
Conclusions:
- GDF15 targeting with GFRAL-Fc is a promising strategy to overcome checkpoint inhibitor resistance in HCC.
- GFRAL-Fc offers multimodal therapeutic benefits, including metabolic regulation and immune remodeling.
- This approach provides a clinically translatable method to optimize PD-1-based regimens for HCC treatment.
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