Zhang Yanhong, Yue Changli, Krichevsky Anna M, Garkavtsev Igor
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Neurology, Ann Romney Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Mol Oncol. 2021 Feb 1;19(2):558-71. doi: 10.1002/1878-0261.12915.
Mounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule-associated protein G3BP2 is involved in the regulation of tumor-initiating (stem) cells. In this study, we show that this protein also upregulates the immune checkpoint molecule PD-L1 under conditions of stress in breast and glioblastoma cancer cells, revealing a previously unknown connection between stemness programs, stress responses, and immune checkpoint control. We also identified a significant correlation between G3BP2 and PD-L1 co-expression in tumor tissues from cancer patients. To assess the targetability of G3BP2, we employed a small molecule (C108) that binds G3BP2 and interferes with the stress response. Tumors treated with C108 had increased CD8 T-cell proliferation and infiltration. Moreover, treatment of breast tumor-bearing mice with C108 resulted in a significant survival benefit and long-term cures. Cancer cells treated with C108 or cancer cells with genetically repressed G3BP2 had decreased PD-L1 expression due to enhanced mRNA degradation. Our study provides a compelling mechanism linking stress granule formation and immune checkpoint program of cancer, suggesting this link may provide new opportunities for improving anticancer immunotherapy.
越来越多的证据表明癌症干性与免疫抑制有关，但其背后的潜在机制尚不清楚。我们之前报道过，应激颗粒相关蛋白G3BP2参与肿瘤起始（干）细胞的调控。在本研究中，我们发现该蛋白在乳腺癌和胶质母细胞瘤细胞受到应激的情况下还会上调免疫检查点分子PD-L1，揭示了干性程序、应激反应和免疫检查点控制之间此前未知的联系。我们还在癌症患者的肿瘤组织中发现G3BP2与PD-L1共表达之间存在显著相关性。为了评估G3BP2的靶向性，我们使用了一种与G3BP2结合并干扰应激反应的小分子（C108）。用C108处理的肿瘤中CD8 T细胞增殖和浸润增加。此外，用C108治疗携带乳腺肿瘤的小鼠可带来显著的生存益处并实现长期治愈。用C108处理的癌细胞或G3BP2基因被抑制的癌细胞由于mRNA降解增强而导致PD-L1表达降低。我们的研究提供了一个将应激颗粒形成与癌症免疫检查点程序联系起来的令人信服的机制，表明这种联系可能为改善抗癌免疫疗法提供新的机会。
