Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai 980-8575, Japan.
Redox Biol. 2023 Nov;67:102904. doi: 10.1016/j.redox.2023.102904. Epub 2023 Oct 10.
In human cancer, activating mutations in the KEAP1-NRF2 pathway are frequently observed, and positively selected for, as they confer the cytoprotective functions of the transcription factor NRF2 on the cancer cells. This results in the development of aggressive tumours which are resistant to treatment with chemotherapeutic compounds. Recent clinical developments have also revealed that NRF2-activated cancers are similarly resistant to immune checkpoint inhibitor drugs. As the mechanism of action of these immune modulating therapies is tangential to the classical cytoprotective function of NRF2, it is unclear how aberrant NRF2 activity could impact the anti-cancer functionality of the immune system. In this context, we found that in human cancer, NRF2-activated cells are highly immunoedited, which allows the cancer cells to escape immune surveillance and develop into malignant tumours. This immunoediting takes the form of reduced antigen presentation by the MHC-I complex, coupled with reduced expression of activating ligands for NK cells. Together, these modifications to the immunogenicity of NRF2-activated cancers inhibit immune effector cell infiltration and engagement, and contribute to the formation of the immunologically cold tumour microenvironment which is a characteristic feature of NRF2-activated cancers.
在人类癌症中，KEAP1-NRF2 通路的激活突变经常被观察到，并被积极选择，因为它们赋予了转录因子 NRF2 的细胞保护功能，使癌细胞具有侵袭性，并对化疗药物产生耐药性。最近的临床发展也揭示了 NRF2 激活的癌症对免疫检查点抑制剂药物同样具有耐药性。由于这些免疫调节治疗的作用机制与 NRF2 的经典细胞保护功能无关，因此尚不清楚异常的 NRF2 活性如何影响免疫系统的抗癌功能。在这种情况下，我们发现在人类癌症中，NRF2 激活的细胞高度免疫编辑，这使得癌细胞能够逃避免疫监视并发展成恶性肿瘤。这种免疫编辑表现为 MHC-I 复合物的抗原呈递减少，同时 NK 细胞的激活配体表达减少。这些对 NRF2 激活的癌症免疫原性的修饰共同抑制了免疫效应细胞的浸润和参与，并导致免疫冷肿瘤微环境的形成，这是 NRF2 激活的癌症的一个特征。
