Gefitinib Reverses PD-L1-Mediated Immunosuppression Induced by Long-term Glutamine Blockade in Bladder Cancer
Guofeng Ma1,2, Huiqing Jia3, Zhiqiang Li4
1Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Abstract:
Glutamine is a major energy source for tumor cells, and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. In this study, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) inhibited the growth of bladder cancer cells in vitro in several ways. In addition, we observed inhibition of tumor growth in bladder cancer-bearing mice by using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade upregulated PD-L1 expression in bladder cancer cells by accumulating reactive oxygen species, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combination treatment of JHU083 and gefitinib reversed the upregulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade, resulting in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings show promise for glutamine metabolism targeting as a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.
Insights
Blocking glutamine metabolism inhibits bladder cancer growth. This strategy, combined with gefitinib, reverses PD-L1 upregulation and enhances anti-tumor immunity for improved therapeutic outcomes.
Area of Science:
- Oncology
- Cancer Metabolism
- Immunotherapy
Background:
- Glutamine is a critical energy source for tumor cells, making its metabolism a target for cancer therapy.
- The role of glutamine metabolism blockade in bladder cancer's malignant progression and immune response remains largely unexplored.
Purpose of the Study:
- To investigate the impact of glutamine metabolism blockade on bladder cancer progression and antitumor immunity.
- To elucidate the mechanisms underlying glutamine blockade-induced changes in PD-L1 expression and T-cell activity.
- To evaluate the efficacy of combining glutamine blockade with gefitinib for enhanced bladder cancer treatment.
Main Methods:
- In vitro treatment of bladder cancer cells with 6-diazo-5-oxo-L-norleucine (DON).
- In vivo studies using bladder cancer xenografts in mice treated with JHU083 (a DON prodrug).
- Analysis of PD-L1 expression, reactive oxygen species (ROS) levels, and the EGFR/ERK/C-Jun signaling pathway.
- Assessment of T-cell activation and immunosuppression.
- Combination therapy with JHU083 and gefitinib.
Main Results:
- Glutamine metabolism blockade (DON/JHU083) inhibited bladder cancer cell growth and tumor progression.
- Prolonged glutamine blockade led to increased PD-L1 expression on bladder cancer cells, correlating with T-cell immunosuppression.
- Mechanistically, glutamine blockade induced PD-L1 upregulation via ROS accumulation and activation of the EGFR/ERK/C-Jun pathway.
- Combination therapy with JHU083 and gefitinib reversed PD-L1 upregulation, alleviated T-cell suppression, and significantly improved therapeutic outcomes.
Conclusions:
- Targeting glutamine metabolism is a promising therapeutic strategy for bladder cancer.
- Glutamine blockade can enhance PD-L1 expression and suppress antitumor immunity, necessitating combination strategies.
- Combining glutamine metabolism inhibition with gefitinib offers a potent approach to overcome immunosuppression and improve bladder cancer treatment efficacy.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...