WCLC 2025 - Posters & ePosters-EP.03.02 An Integrating Multiomic Approach to Chart the Tumor Immune Microenvironment Associated to Immunotherapy Response in Non-Small Cell Lung Cancer

EP.03.02 An Integrating Multiomic Approach to Chart the Tumor Immune Microenvironment Associated to Immunotherapy Response in Non-Small Cell Lung Cancer

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This study employs an integrative multiomic approach to characterize the Tumor Immune MicroEnvironment (TIME) in Non-Small Cell Lung Cancer (NSCLC), focusing on features associated with response to immune checkpoint blockade (ICB) therapy. TIME composition and structure, particularly the presence of tertiary lymphoid structures (TLS)—specialized immune cell aggregates involved in robust antitumor immunity—are key determinants of clinical outcomes and therapy efficacy.<br /><br />Researchers analyzed paired tumor, adjacent non-tumor tissues, and peripheral blood mononuclear cells from NSCLC patients undergoing curative surgery, some of whom later received ICB following recurrence. Using spatial transcriptomics (GeoMx DSP, 10X Visium), single-cell RNA sequencing, and immunohistochemistry, they examined TIME components including B cell subsets and cancer-associated fibroblasts (CAFs).<br /><br />Key findings show that NSCLC patients classified as super good (SG) responders to ICB exhibit TLS with higher maturation and activation markers, notably increased germinal center (GC) and switched memory B cells (SwBm), compared to poor responders (PR). Spatial mapping coupled with single-cell atlases revealed distinct B cell profiles in TLS regions correlating with response categories.<br /><br />Importantly, CAFs were found to have heterogeneous subsets with differing impacts on TIME. A particular CAF cluster overexpressed hMENA (encoded by ENAH), an actin cytoskeleton regulator linked to lymphotoxin β receptor (LTβR) expression and CXCL13 secretion, factors critical for TLS development. Poor responders showed increased immunosuppressive hMENA-overexpressing CAFs both inside and outside TLS compared to SG responders.<br /><br />Overall, the study delineates a TIME landscape where mature TLS and favorable B cell profiles associate with positive ICB responses, while high presence of immunosuppressive CAFs correlates with resistance. This comprehensive multiomic mapping of immune and stromal elements offers insights for predictive biomarkers and potential targets to improve immunotherapy effectiveness in NSCLC.

Asset Subtitle

Riccardo Taje'

Meta Tag

Speaker Riccardo Taje'

Topic Tumor Biology – Translational Biology

Keywords

Tumor Immune MicroEnvironment

Non-Small Cell Lung Cancer

immune checkpoint blockade

tertiary lymphoid structures

B cell subsets

cancer-associated fibroblasts

spatial transcriptomics

single-cell RNA sequencing

hMENA

immunotherapy resistance