Gefitinib Reverses PD-L1-Mediated Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer

谷氨酰胺 癌症研究 膀胱癌 药理学 癌症 医学 免疫抑制 癌细胞 免疫疗法 封锁 吉非替尼 表皮生长因子受体 免疫学 生物 内科学 受体 生物化学 氨基酸
作者
Guofeng Ma,Huiqing Jia,Zhiqiang Li,Xiangyan Zhang,Liping Wang,Zhilei Zhang,Yujing Xiao,Zhijuan Liang,Dan Li,Yuanbin Chen,Xintao Tian,Yonghua Wang,Ye Liang,Haitao Niu
出处
期刊:Cancer immunology research [American Association for Cancer Research]
标识
DOI:10.1158/2326-6066.cir-24-0039
摘要

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. Here, 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 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 up-regulated PD-L1 expression in bladder cancer cells by accumulating ROS, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combination treatment of JHU083 and gefitinib reversed the up-regulation 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.
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