Feasibility Study of Intratumoral NRF2 Expression as a Predictive Biomarker for the Effectiveness of Immunotherapy in Patients with Non-Small Cell Lung Cancer Treated with PD-1 Inhibitor

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy.