Wang Kewei, Li Zixi, Xuan Ying, Zhao Yong, Deng Chao, Wang Meidan, Xie Chenjun, Yuan Fenglai, Pang Qingfeng, Mao Wenjun, Cai Dongyan, Zhong Zhangfeng, Mei Jie
Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China.
Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
Cancer Cell Int. 2023 Oct 4;23(1):229. doi: 10.1186/s12935-023-03056-9.
Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers.
The study with the largest sample size (n = 49,533) explored the landscape of NFE2L2 mutations and their impact response/resistance to ICIs using public cohorts. In addition, the in-house WXPH cohort was used to validate the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC.
In two pan-cancer cohorts, Nrf2-activating mutation was associated with higher TMB value compared to wild-type. We identified a significant association between Nrf2-activating mutation and shorter overall survival in pan-cancer patients and NSCLC patients but not in those undergoing ICIs treatment. Similar findings were obtained in cancer patients carrying the NFE2L2 mutation. Furthermore, in NSCLC and other cancer cohorts, patients with NFE2L2 mutation demonstrated more objective responses to ICIs than patients with wild type. Our in-house WXPH cohort further confirmed the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Lastly, decreased inflammatory signaling pathways and immune-depleted immunological microenvironments were enriched in Nrf2-activating mutation patients with NSCLC.
Our study found that patients with Nrf2-activating mutation had improved immunotherapy outcomes than patients with wild type in NSCLC and other tumor cohorts, implying that Nrf2-activating mutation defined a distinct subset of pan-cancers and might have implications as a biomarker for guiding ICI treatment, especially NSCLC.
KEAP1-NFE2L2信号通路中的突变与肿瘤发生增加和侵袭性增强有关。有趣的是，并非NFE2L2上的所有热点突变都具有损害性；有些甚至具有激活作用。然而，关于NFE2L2突变与Nrf2激活突变之间的关联以及非小细胞肺癌（NSCLC）和其他多种癌症对免疫检查点抑制剂（ICI）的反应性，存在相互矛盾的证据。
该样本量最大的研究（n = 49,533）利用公开队列探索了NFE2L2突变情况及其对ICI的反应/抗性影响。此外，使用内部的WXPH队列来验证免疫疗法对NFE2L2突变的NSCLC患者的疗效。
在两个泛癌队列中，与野生型相比，Nrf2激活突变与更高的肿瘤突变负荷（TMB）值相关。我们发现Nrf2激活突变与泛癌患者和NSCLC患者的总生存期缩短显著相关，但在接受ICI治疗的患者中并非如此。在携带NFE2L2突变的癌症患者中也获得了类似的结果。此外，在NSCLC和其他癌症队列中，NFE2L2突变的患者对ICI的客观反应比野生型患者更多。我们的内部WXPH队列进一步证实了免疫疗法对NFE2L2突变的NSCLC患者的疗效。最后，在Nrf2激活突变的NSCLC患者中，炎症信号通路减少和免疫耗竭的免疫微环境增多。
我们的研究发现，在NSCLC和其他肿瘤队列中，Nrf2激活突变的患者比野生型患者的免疫治疗结果更好，这意味着Nrf2激活突变定义了一个独特的泛癌亚组，可能作为指导ICI治疗的生物标志物，尤其是在NSCLC中。
