Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) is a key biomarker for lung cancer immunotherapy.
• Intratumoral heterogeneity of PD-L1 expression complicates its utility and understanding of the tumor microenvironment (TME).

Purpose of the Study:

• To investigate the spatial heterogeneity of the lung cancer TME in relation to PD-L1 expression on TCs.
• To identify distinct molecular and cellular features of TCs and immune cells (ICs) within different PD-L1 expression contexts.
• To discover prognostic biomarkers and predict immunotherapy response in lung cancer.

Main Methods:

• Proteomic and whole-transcriptomic digital spatial profiling of TCs and ICs in spatially matched areas.
• Analysis based on tumor PD-L1 expression levels and immune microenvironment status.
• Validation using immunohistochemistry (IHC), The Cancer Genome Atlas (TCGA), and immunotherapy cohorts.

Main Results:

• ICs in high PD-L1 areas exhibited more immunosuppressive and exhausted features compared to those in low PD-L1 areas.
• TCs with high PD-L1 showed distinct pathway activations (pro-inflammatory vs. metabolic) depending on the immune context (inflamed vs. deficient).
• A prognostic gene signature for lung cancer was identified, and a high CD8+/M2 macrophage ratio predicted favorable outcomes in patients receiving immunotherapy.

Conclusions:

• Distinct spatial features of TCs and ICs within the lung TME are associated with PD-L1 expression and immune infiltration.
• Understanding spatial heterogeneity is crucial for optimizing lung cancer immunotherapy biomarkers and treatment strategies.
• The identified gene signature and immune cell ratio offer potential prognostic and predictive value.