Heterogeneous expression of immunotherapy response markers in non-small cell lung cancer with hyperactive NRF2...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Activating mutations in the NRF2 pathway are linked to aggressive non-small cell lung cancer (NSCLC), poor prognosis, and resistance to immune checkpoint inhibitors (ICI).
• The NRF2 pathway's role in the tumor microenvironment and its interaction with ICI response markers remain incompletely understood in NSCLC.

Purpose of the Study:

• To investigate the heterogeneity of ICI response markers and tumor-infiltrating immune cells in NSCLC with hyperactive NRF2.
• To determine the relationship between NRF2 activity and immune gene signatures associated with ICI response.
• To identify potential NSCLC subsets that may benefit from ICI therapy despite NRF2 pathway activation.

Main Methods:

• Utilized a validated NRF2 transcriptional signature and a curated 47-gene ICI-Immune signature.
• Performed protein association network and gene expression correlation analyses.
• Categorized NSCLC into NRF2-low and NRF2-high groups and performed clustering based on NRF2 and ICI-Immune scores.
• Conducted histopathological analysis on 103 NSCLC cases.
• Investigated PD-L1 expression in KEAP1-mutated cell lines and omics data.

Main Results:

• NRF2 and ICI-Immune gene sets function as independent transcriptional modules with no significant correlation.
• NRF2-high NSCLC cases generally exhibit an immune-depleted tumor microenvironment, but a subset ('NRF2-high/ICI-Immune-high') displays features of ICI responsiveness, including PD-L1 upregulation and increased immune infiltrates.
• This 'NRF2-high/ICI-Immune-high' subset constitutes approximately one-third of NRF2-high cases and shows characteristics of the C2/IFNγ-dominant tumor-immune subtype.
• Histopathological analysis identified NRF2-high/PD-L1+ tumors with increased tumor-infiltrating lymphocytes (TILs), potentially representing the NRF2-high/ICI-Immune-high subset.
• In vitro experiments indicated that constitutive NRF2 activation does not dictate PD-L1 mRNA/protein levels.

Conclusions:

• Hyperactive NRF2 in NSCLC leads to a diverse tumor microenvironment, with distinct immune profiles.
• A subset of NRF2-high NSCLC patients ('NRF2-high/ICI-Immune-high') possess molecular and histological features suggesting potential responsiveness to ICI therapy.
• These findings offer a potential histology-based approach to identify ICI responders within the NRF2-mutated NSCLC population.