WCLC 2025 - Posters & ePosters-EP.12.39 Dynamic Evolution of Genomic and Microenvironment Landscape in ALK-Positive Non-Small Cell Lung Cancer

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This study investigates the dynamic genomic and tumor microenvironment (TME) changes in ALK-positive non-small cell lung cancer (NSCLC) before and after tyrosine kinase inhibitor (TKI) treatment. Specimens from 16 ALK-positive patients (baseline and post-TKI) and baseline samples from 28 ALK-negative NSCLC patients underwent RNA and whole-exome sequencing.<br /><br />Comparative analysis reveals distinct TME profiles between ALK-positive and ALK-negative NSCLC. ALK-positive tumors exhibit high antigen presentation capacity but low tumor mutation burden (TMB), reduced plasma cell and CD8+ T cell infiltration, and upregulated immunosuppressive elements such as increased M2 macrophages, exhausted T cells, and TGFβ secretion. In contrast, ALK-negative NSCLC shows elevated T cells, B cells, NK cells, and higher TMB.<br /><br />Longitudinal profiling of an ALK-positive patient during TKI therapy indicated no specific mutational signatures associated with resistance but identified changes in immune cell populations—particularly CD8+ T cells and dendritic cells—that may signal emerging TKI resistance. The immune microenvironment under ALK-TKI pressure shows dynamic shifts: response timepoints correlate with increased CD8+ T cells, B cells, dendritic cells, and low TMB, whereas non-response timepoints associate with particular mutation signatures (1 and 16) and upregulated estrogen signaling pathways.<br /><br />Notably, estrogen signaling activation is enriched in ALK-TKI resistant tumors. Patients with higher estrogen receptor scores experienced poorer progression-free survival under ALK-TKI treatment, suggesting estrogen pathway involvement in resistance mechanisms.<br /><br />In summary, ALK-positive NSCLC displays a unique immunosuppressive TME with dynamic evolution during TKI treatment. Immune cell infiltration patterns and estrogen signaling pathways are linked to treatment response and resistance. These findings highlight potential biomarkers and therapeutic targets to overcome resistance and improve ALK-positive NSCLC management.

Asset Subtitle

Jiani Wu

Meta Tag

Speaker Jiani Wu

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

ALK-positive NSCLC

tumor microenvironment

tyrosine kinase inhibitor

immune cell infiltration

tumor mutation burden

M2 macrophages

estrogen signaling pathway

TKI resistance

progression-free survival

biomarkers