Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

Baird, Liam; Yamamoto, Masayuki

doi:10.1016/j.redox.2023.102904

Cited by 8 publications

(3 citation statements)

References 66 publications

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“…Intriguingly, there is also diminished expression of IFN-responsive proteins including B2M, PD-L1, PD-L2, STING, and IRF3 in CPN samples. The downregulation of B2M, a component of the MHC class I molecule necessary for tumor antigen presentation, provides further evidence to support that constitutive NRF2 activity in this GEMM may have both oncogenic and immunoevasive properties, a phenomenon that has been recently reported in human cancers ( 53 ).…”

Section: Discussionsupporting

confidence: 64%

NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma

Hamad,

Sellers,

Wamsley

et al. 2024

Cancer Research Communications

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Aberrant activation of the NRF2/NFE2L2 transcription factor commonly occurs in head and neck squamous cell carcinomas (HNSCCs). Mouse model studies have shown that NRF2 activation alone does not result in cancer. When combined with classic oncogenes and at the right dose, NRF2 activation promotes tumor initiation and progression. Here we deleted the tumor suppressor genes p16INK4A and p53 (referred to as CP mice), which are commonly lost in human HNSCC, in the presence of a constitutively active NRF2E79Q mutant (CPN mice). NRF2E79Q expression in CPN mice resulted in squamous cell hyperplasia or dysplasia with hyperkeratosis in the esophagus, oropharynx, and forestomach. In addition, CPN mice displayed oral cavity squamous cell carcinoma (OSCC); CP mice bearing wild type NRF2 expression did not develop oral cavity hyperplasia, dysplasia or OSCC. In both CP and CPN mice, we also observed predominantly abdominal sarcomas and carcinomas. Our data show that in the context of p53 and p16 tumor suppressor loss, NRF2 activation serves oncogenic functions to drive OSCC. CPN mice represent a new model for OSCC that closely reflects the genetics of human HNSCC.

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Section: Discussionsupporting

confidence: 64%

NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma

Hamad,

Sellers,

Wamsley

et al. 2024

Cancer Research Communications

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“…Context plays an extremely important role in determining whether activation of the pathway has pro- or anti-tumor effects. Although NRF2 activation in cancer cells can promote drug resistance and tumor cell survival, NRF2 activation in the microenvironment can have the opposite effect [ 18 , 19 , 44 , 45 , 46 , 47 ]. As immune cells are particularly sensitive to the high levels of oxidative stress in the tumor microenvironment [ 11 , 12 , 13 , 48 , 49 , 50 , 51 ], NRF2 activation in immune cells can increase their tolerance of the harsh environment and facilitate an anti-tumor immune response.…”

Section: Discussionmentioning

confidence: 99%

The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer

Moerland,

Liby

2024

Antioxidants

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NRF2 activation protects epithelial cells from malignancy, but cancer cells can upregulate the pathway to promote survival. NRF2 activators including CDDO-Methyl ester (CDDO-Me) inhibit cancer in preclinical models, suggesting NRF2 activation in other cell types may promote anti-tumor activity. However, the immunomodulatory effects of NRF2 activation remain poorly understood in the context of cancer. To test CDDO-Me in a murine model of established lung cancer, tumor-bearing wildtype (WT) and Nrf2 knockout (KO) mice were treated with 50–100 mg CDDO-Me/kg diet, alone or combined with carboplatin/paclitaxel (C/P) for 8–12 weeks. CDDO-Me decreased tumor burden in an Nrf2-dependent manner. The combination of CDDO-Me plus C/P was significantly (p < 0.05) more effective than either drug alone, reducing tumor burden by 84% in WT mice. CDDO-Me reduced the histopathological grade of WT tumors, with a significantly (p < 0.05) higher proportion of low-grade tumors and a lower proportion of high-grade tumors. These changes were augmented by combination with C/P. CDDO-Me also protected WT mice from C/P-induced toxicity and improved macrophage and T cell phenotypes in WT mice, reducing the expression of CD206 and PD-L1 on macrophages, decreasing immunosuppressive FoxP3+ CD4+ T cells, and increasing activation of CD8+ T cells in a Nrf2-dependent manner.

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“…HBXIP reduces ROS levels in tamoxifen-resistant breast cancer cells, demonstrating its potential antioxidant capacity ( 70 ). The KEAP1-NRF2 signaling pathway is commonly dysregulated in tumor cells to maintain oxidative balance ( 71 ). In breast cancer, HBXIP competitively binds to KEAP1 and NRF2, with a significantly higher affinity for KEAP1 than NRF2 ( 60 ).…”

Section: Hbxip and Tumorsmentioning

confidence: 99%

Research progress on oncoprotein hepatitis B X‑interacting protein (Review)

Cheng,

Guo,

Zou

et al. 2024

Mol Med Rep

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Hepatitis B X-interacting protein (HBXIP) is a membrane protein located on the lysosomal surface and encoded by the Lamtor gene. It is expressed by a wide range of tumor types, including breast cancer, esophageal squamous cell carcinoma and hepatocellular carcinoma, and its expression is associated with certain clinicopathological characteristics. In the past decade, research on the oncogenic mechanisms of HBXIP has increased and the function of HBXIP in normal cells has been gradually elucidated. In the present review, the following was discussed: The normal physiological role of the HBXIP carcinogenic mechanism; the clinical significance of high levels of HBXIP expression in different tumors; HBXIP regulation of transcription, post-transcription and post-translation processes in tumors; the role of HBXIP in improving the antioxidant capacity of tumor cells; the inhibition of ferroptosis of tumor cells and regulating the metabolic reprogramming of tumor cells; and the role of HBXIP in promoting the malignant progression of tumors. In conclusion, the present review summarized the existing knowledge of HBXIP, established its carcinogenic mechanism and discussed future related research on HBXIP.

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Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

Cited by 8 publications

References 66 publications

NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma

NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma

The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer

Research progress on oncoprotein hepatitis B X‑interacting protein (Review)

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