CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Diffuse Pleural Mesothelioma (DPM) is a rare, incurable cancer with limited treatment options.
• Immune checkpoint inhibitors (ICIs) show efficacy in a subset of DPM patients, highlighting the need for predictive biomarkers.
• CDKN2A gene deletion is a frequent event in DPM and is associated with an immunosuppressive phenotype.

Purpose of the Study:

• To investigate the impact of CDKN2A deletion (CDKN2Adel) on the spatial organization and function of the immune infiltrate in DPM.
• To evaluate the potential of CDKN2Adel as a predictive biomarker for ICI response in DPM.

Main Methods:

• Retrospective analysis of 89 DPM patients, assessing CDKN2Adel via digital droplet PCR.
• Comprehensive immune-profiling using 770 immune-related genes.
• Morphologically resolved, high-dimensional transcriptomics to reconstruct spatial immune-tumor interactions.

Main Results:

• CDKN2Adel was present in 41.5% of DPM cases and correlated with reduced survival.
• CDKN2Adel samples showed significant downregulation of immune-related genes, indicating immune deprivation.
• Spatial transcriptomics revealed that CDKN2Adel profoundly alters immune microenvironment organization, reducing immune infiltration and signaling, particularly in sarcomatoid lesions.

Conclusions:

• CDKN2A deletion significantly impacts the spatial organization of the immune microenvironment in DPM.
• The observed immune depletion and altered signaling due to CDKN2Adel support its potential as a predictive biomarker for ICI therapy.
• Further validation is warranted to implement CDKN2Adel as a clinical tool for predicting ICI response in DPM.