WCLC 2025 - Posters & ePosters-EP.02.04 Identification of a Novel Immunotherapy Target in EGFR-Mutant Lung Cancer Resistant to Immune Checkpoint Inhibitors

EP.02.04 Identification of a Novel Immunotherapy Target in EGFR-Mutant Lung Cancer Resistant to Immune Checkpoint Inhibitors

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This study investigates a novel immunotherapy target in EGFR-mutant non-small cell lung cancer (NSCLC), which is typically resistant to immune checkpoint inhibitors (ICIs). EGFR-mutant lung cancers often show low PD-L1 expression and low tumor mutation burden, contributing to this resistance. Emerging evidence suggests an immunosuppressive tumor microenvironment (TME) plays a role, but mechanisms remain unclear. <br /><br />Using TCGA and CCLE datasets, the researchers identified a gene, referred to as "Gene X," significantly upregulated in EGFR-mutant lung adenocarcinomas compared to non-EGFR tumors. Analysis of the EGFR-mutant HCC2279 cell line (with exon 19 deletion) revealed two subpopulations based on Gene X expression: high (X-High) and low (X-Low). These subpopulations displayed distinct morphological differences in vitro.<br /><br />RNA sequencing comparing X-High and X-Low cells showed enrichment of immune- and proliferation-related pathways in X-High cells. Functional assays using co-culture of HCC2279 cells with NK-92 natural killer (NK) cells in both 2D and 3D spheroid cultures demonstrated that Gene X impacts NK cell migration and infiltration. Knockout or inhibition of Protein X in X-High cells increased NK cell migration towards tumor spheroids, indicating that Protein X suppresses NK cell-mediated anti-tumor immune response.<br /><br />In conclusion, Protein X is upregulated specifically in EGFR-mutant lung cancer and contributes to immune evasion by impairing NK cell migration and infiltration. These findings suggest that Protein X is a novel immunotherapy target to overcome resistance to ICIs in EGFR-mutant NSCLC. Future work aims to elucidate the detailed function of Protein X in vivo and validate its role in modulating immune cell dynamics within the tumor microenvironment, potentially leading to new therapeutic strategies for this hard-to-treat cancer subset.

Asset Subtitle

Kiichi Nitanai

Meta Tag

Speaker Kiichi Nitanai

Topic Tumor Biology – Preclinical Biology

Keywords

EGFR-mutant NSCLC

immune checkpoint inhibitors resistance

Gene X

Protein X

tumor microenvironment

NK cell migration

immune evasion

lung adenocarcinoma

RNA sequencing

immunotherapy target