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Updated: Sep 9, 2025
Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
Published on: October 2, 2015
CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma
Federica Torricelli1, Benedetta Donati1, Veronica Manicardi1
1Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
Introduction:
Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM.
Methods:
A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples.
Results:
CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival (p = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions.
Conclusion:
These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.
Insights
Deletion of the CDKN2A gene in diffuse pleural mesothelioma (DPM) creates an immunosuppressive tumor microenvironment. This CDKN2A deletion impairs immune cell infiltration and signaling, suggesting its potential as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy response.
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.
