Notebook: Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

Dr. Best S A et al recently report their finding on NSCLC and KEAP1/NRF2 and PI3K Pathways[1].

  It is well known that non-small cell lung cancer is the most common type of lung cancer, with a lower survival rate in most cancer.Adenocarcinoma (ADC) is the major histological subtype of lung cancer and the KEAP1/NRF2 pathway have some alterations in 23% Adenocarcinoma cases. KEAP1 and NRF2 are related to oxidative stress [2]. NRF2 is a master regulator of the antioxidant response and it is negatively regulated by KEAP1. Some studies have shown that cancers with high NRF2 levels is related to poor prognosis, and NRF2 can promote cell proliferation by augment expression of metabolic genes [3].In the same time, PI3K pathway alterations and mutations of PTEN were also found in human lung ADCs [2]. Best et al. studied the changes and interconnections of these factors on the exploration of cancer-driven and the improvement of therapeutic effects [1].

  Firstly, the authorsused a conditional gene-targeting approach to investigate whether combined activation of PIK3 pathways and Keap1/Nrf2 can promote lung tumorigenesis. It was found that Keap1f/f/Ptenf/fmice showed a significant increase of lung weight comparing with other groups. HE staining, flow cytometry and qRT-PCR analysis revealed tumor tissue proliferation, mRNA expression of related markers and an increase number of bronchiole epithelial cells. These data proved that the tumor of K1P mice were from bronchiole epithelial cells. So, the simultaneous absence of Keap1 and Pten can promote tumor formation.

  The high expression of Nqo1 and p-Akt revealed that loss of keap1 and Pten can lead to activation of Keap1/Nrf2 and PI3K/Pten pathways. By qRT-PCR analysis, the authors found Nqo1 was significantly augment when both Keap1 and Ptenwere lost. And the absence of Pten can enhance the stability of Nrf2Detection of plasma metabolites in mice showed that changes in PPP metabolism are associated with stability of Nrf2.The Cancer Genome Atlas (TCGA) expression data could also prove it too. Nrf2 stabilization leads to significant changes in tumor metabolism and enhanced pentose phosphate pathway activity.

  The article also studied the situation of the immune microenvironment in Keap1/Pten Lungs. The immune cell representationwould decrease in NQO1highADC, and most immune subsets are reduced too. Interestingly, this study detected a decrease in lymphoid cell subsets in lungs, CD8 T cells expressed high levels of PD-1 and tumor cells had significantly increased PD-L1 expression in K1P group. And for the review of the reported data, K1P modelcan be good to reflect the important immunological features of human NSCLC.

  Finally,in order to explore whether immune suppression in K1P tumor-bearing lungs was related the enhanced PD-L1 expression, the authors used a combination immunotherapy (PD-1 and CTLA-4 pathway blockade) in K1P model. The results showed that anti-PD-1/anti-CTLA-4 treatment group had a good immunotherapy response, such as the decrease of tumor burden and lung weight. Besides, the treatment was accompanied by an increase in the number of infiltrating lymphoid cells and a decrease of PD-L1 expression on tumor cells in the lungs. In short, these data highlight that KEAP1/NRF2 tumors are sensitive to immuno-therapy.

References

1.Best S A, De Souza D P, Kersbergen A, et al. Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment[J]. Cell metabolism, 2018, 27(4): 935-943. e4.

2.Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma[J]. Nature, 2014, 511(7511): 543.

3.Mitsuishi Y, Taguchi K, Kawatani Y, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming[J]. Cancer cell, 2012, 22(1): 66-79.