Defining Non-small Cell Lung Cancer Tumor Microenvironment Changes at Primary and Acquired Immune Checkpoint...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Immune checkpoint inhibitors (ICI) are effective for non-small cell lung cancer (NSCLC).
• Tumor microenvironment (TME) changes in primary and acquired ICI resistance are understudied.
• Tissue biopsy collection at disease progression is challenging.

Purpose of the Study:

• To investigate the TME differences in primary versus acquired ICI resistance in advanced-stage NSCLC.
• To identify potential biomarkers and therapeutic targets for overcoming ICI resistance.

Main Methods:

• Leveraged clinical and real-world data from three NSCLC cohorts (Tempus, CANOPY-1, SU2C).
• Analyzed treatment outcome information and tissue RNA sequencing data.
• Compared TME characteristics at primary and acquired resistance states.

Main Results:

• Acquired resistance is associated with higher IFNγ and T-cell exhaustion.
• Primary resistance shows lower B-cell and dendritic cell expression, potentially due to prior platinum-based chemotherapy.
• Baseline transcriptomics suggest innate immune cells are important in PD-L1<1% NSCLC, while IFNγ and T-cell inflammation predict outcomes in PD-L1≥1% NSCLC.

Conclusions:

• Significant divergence in TME observed between primary and acquired ICI resistance.
• Myeloid cells may play a crucial role in ICI resistance in the PD-L1<1% NSCLC population.
• Findings provide insights for developing next-generation therapies to overcome ICI resistance.