Liang Beiyuan, Khan Misbah, Storts Hayden, Zhang Evan H, Zheng Xinru, Xing Xuanxuan, Claybon Hazel, Wilson Jenna, Li Chunjie, Jin Ning, Fishel Richard, Miles Wayne O, Wang Jing J
Department of Cancer Biology and Genetics, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
Division of Medical Oncology, Department of Internal Medicine, James Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, Ohio.
Mol Cancer Ther. 2025 Jan 2;24(1):131-140. doi: 10.1158/1535-7163.MCT-24-0289.
Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.
结直肠癌是美国癌症死亡的第二大主要原因。尽管包括抗PD-1/PD-L1在内的免疫检查点阻断疗法已成功治疗了一部分结直肠癌患者，但其缓解率仍然较低。我们发现，利鲁唑是一种经美国食品药品监督管理局（FDA）批准、耐受性良好的治疗肌萎缩侧索硬化症的口服药物，它能增加同基因免疫活性小鼠肿瘤内的CD8+ T细胞，并抑制结肠癌细胞的肿瘤生长。利鲁唑介导的肿瘤抑制依赖于CD8+ T细胞的存在。利鲁唑激活结肠癌细胞中的胞质DNA感应环磷酸鸟苷-腺苷酸合成酶（cGAS）/干扰素基因刺激物（STING）途径，导致IFNβ及包括CXCL10在内的IFNβ调节基因的表达增加。抑制共济失调毛细血管扩张症突变基因（ATM）而非ATM相关基因，会导致IFNβ表达协同增加，这表明利鲁唑诱导了有助于cGAS/STING激活的ATM介导的损伤反应。cGAS或STING的缺失显著减弱了利鲁唑诱导的IFNβ和CXCL10表达，以及肿瘤内CD8+ T细胞的增加和肿瘤生长的抑制。这些结果表明，利鲁唑介导的CD8+ T细胞肿瘤浸润和肿瘤生长减弱依赖于肿瘤细胞内在的STING激活。为了确定利鲁唑治疗是否能使肿瘤微环境对免疫检查点调节产生预激作用，将利鲁唑与抗PD-1治疗联合使用。这种联合治疗比任何一种单一药物都显示出更高的疗效，并在体内强烈抑制了肿瘤生长。综上所述，我们的研究表明，利鲁唑激活cGAS/STING介导的先天性免疫反应，这可能被用于使结直肠癌对抗PD-1/PD-L1治疗敏感。
