Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer.
Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer.
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肺癌是癌症相关死亡的主要原因。免疫疗法激活患者的免疫系统来识别和杀死癌细胞。此外，记忆免疫细胞的形成可以防止癌症复发，从而产生持久的反应。然而，只有 20% 的患者从免疫治疗中受益，因为肿瘤源性因子会抑制免疫反应。在此，我们测试了 Withaferin A（一种草药化合物）是否可以使免疫疗法对肺癌患者更有效。我们发现，Withaferin A 会诱导肺癌细胞产生分子，这些分子会增加免疫细胞的浸润，但无法杀死癌细胞。值得注意的是，在免疫功能正常的肺癌小鼠模型中，Withaferin A 和免疫治疗方案的联合治疗在激活免疫细胞和减少肿瘤生长方面显示出比单独免疫治疗更有效的效果。这项研究提出了一种可以进行临床测试以改善肺癌免疫治疗的新方法。晚期肺癌的治疗仍然充满挑战，五年生存率为 8%。免疫检查点阻断剂（ICB）通过重新激活抗肿瘤免疫力，彻底改变了非小细胞肺癌（NSCLC）的治疗。尽管取得了持久的缓解，但由于免疫抵抗，ICB 仅对 20% 的患者有效。因此，目前正在研究克服免疫抵抗的协同组合方法。在此，我们研究了 Withaferin A (WFA)（一种草药化合物）的免疫调节作用及其与 ICB 联合治疗 NSCLC 的有效性。我们的体外结果表明，WFA 会诱导 NSCLC 细胞系中的免疫原性细胞死亡 (ICD)，并增加程序性死亡配体 1 (PD-L1) 的表达。 N-乙酰半胱氨酸 (NAC)（一种活性氧 (ROS) 清除剂）的施用消除了 WFA 诱导的 ICD 和 PD-L1 上调，表明 ROS 参与了这一过程。此外，我们发现 WFA 和 α-PD-L1 的组合可显着减少免疫活性肿瘤模型中的肿瘤生长。我们的结果表明，WFA 增加了 CD-8 T 细胞并减少了浸润肿瘤微环境的免疫抑制细胞。 NAC 的施用部分抑制了联合方案的抗肿瘤反应。总之，我们的结果表明，WFA 部分通过激活 ROS 使 NSCLC 对 α-PD-L1 敏感。
Lung cancer is the leading cause of cancer-related deaths. Immunotherapy activates the patient’s immune system to identify and kill cancer cells. Moreover, memory immune cells are formed that prevent the recurrence of cancer, leading to durable responses. However, only 20% of patients benefit from immunotherapy because the tumor-derived factors suppress the immune response. Herein, we tested if Withaferin A (a herbal compound) can make immunotherapy more effective in lung cancer patients. We found that Withaferin A induces the production of molecules from lung cancer cells that increase the infiltration of immune cells but are not able to kill cancer cells. Notably, in an immunocompetent mouse model of lung cancer, treatment with a combination of Withaferin A and an immunotherapy regimen showed more effectiveness than immunotherapy alone in activating immune cells and reducing tumor growth. This study presents a novel approach that can be tested clinically to improve lung cancer immunotherapy. Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)—a herbal compound—and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.
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影响因子：
5.7
作者：
Kunimasa K;Nagano T;Shimono Y;Dokuni R;Kiriu T;Tokunaga S;Tamura D;Yamamoto M;Tachihara M;Kobayashi K;Satouchi M;Nishimura Y
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3.3
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