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Updated: Aug 5, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Feasibility Study of Intratumoral NRF2 Expression as a Predictive Biomarker for the Effectiveness of Immunotherapy in
Yasuto Jin1, Yukihisa Inoue1, Hiroyuki Shimada1
1Department of Respiratory Medicine, Hiratsuka Kyosai Hospital, 9-11 Oiwake, Hiratsuka 254-8502, Kanagawa, Japan.
Abstract:
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.
Insights
Nuclear factor erythroid 2-related factor 2 (NRF2) overexpression in non-small cell lung cancer (NSCLC) correlates with resistance to PD-1 blockade therapy. Lower NRF2 levels indicate a better response to immune checkpoint inhibitors like nivolumab and pembrolizumab.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) overexpression facilitate cancer immune evasion.
- Anti-PD-1 antibodies (nivolumab, pembrolizumab) show limited response rates in advanced non-small cell lung cancer (NSCLC).
- Biomarkers predicting response to immune checkpoint inhibitors are crucial due to tumor microenvironment heterogeneity.
Purpose of the Study:
- To investigate the association between nuclear factor erythroid 2-related factor 2 (NRF2) expression in NSCLC and clinicopathological factors.
- To evaluate the relationship between NRF2 expression, intratumoral PD-L1 and CD8 levels, and response to anti-PD-1 monotherapy.
- To determine if NRF2 expression can predict treatment efficacy in NSCLC patients receiving PD-1 blockade.
Main Methods:
- Immunohistochemistry was used to assess NRF2, PD-L1, and CD8 expression in tumor cells and tumor-infiltrating lymphocytes.
- The study included 54 patients with advanced NSCLC (adenocarcinoma and squamous cell carcinoma) treated with nivolumab or pembrolizumab.
- Clinicopathological features were compared with the expression levels of the studied markers.
Main Results:
- Weak NRF2 staining significantly correlated with high PD-L1 and CD8+ tumor-infiltrating lymphocytes.
- A favorable response to anti-PD-1 therapy (nivolumab or pembrolizumab) was observed in patients with weak NRF2 expression.
- Progression-free survival varied significantly based on NRF2 expression levels in patients undergoing anti-PD-1 therapy.
Conclusions:
- NRF2 overexpression in NSCLC is linked to resistance against PD-1 blockade monotherapy.
- NRF2 expression serves as a potential predictive biomarker for anti-PD-1 therapy response in NSCLC.
- Targeting the NRF2 pathway may offer new therapeutic strategies for NSCLC patients resistant to current immunotherapies.
