CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma

Our plain-English summary of CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma, by F. Torricelli, B. Donati, V. Manicardi, et al (Journal of Experimental & Clinical Cancer Research, 2025).

The study

• Authors: F. Torricelli, B. Donati, V. Manicardi, M. Gugnoni, F. Reggiani, G. Manzotti, P. Di Chiaro, C. Ascione, S. Piana, R. Valli, R. Piro, M. Paci, N. Facciolongo, F. Lococo, A. Ciarrocchi
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2025;44(1):256
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2025. The Author(s).

In plain English

This retrospective laboratory study examined stored tumor tissue from 89 patients with diffuse pleural mesothelioma treated at one institution, the authors' own in Reggio Emilia, Italy, between 2010 and 2021. The authors tested each tumor for deletion of a gene called CDKN2A and compared immune-related gene activity between tumors with and without the deletion. The deletion was found in 41.6% (37) of tumors and was associated with shorter survival. Of 82 tumors successfully profiled (32 with the deletion, 50 without), 373 genes differed between the groups, and 368 of them were less active in deleted tumors. Estimates of cell types derived from gene activity suggested fewer immune cells, including T cells, B cells, natural killer cells and macrophages, in deleted tumors. A tissue-mapping analysis of 9 tumors found this immune depletion most marked in sarcomatoid areas. The authors concluded that CDKN2A deletion is associated with exclusion of immune cells from the tumor. They proposed testing it, together with tumor type, as a predictor of response to immunotherapy. Table 1 lists most patients with recorded information as asbestos-exposed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-center (monocentric) retrospective cohort study using molecular laboratory analysis of stored tumor tissue: DNA testing for gene deletion, bulk immune gene-expression profiling, and spatial transcriptomics
• Who was studied: 89 patients with diffuse pleural mesothelioma (DPM) treated at the authors' institution from 2010 to 2021, with the institution listed in the author affiliations as AUSL-IRCCS di Reggio Emilia, Italy. 82 were successfully profiled for gene expression. 9 tumors (5 with the deletion, 4 without) underwent spatial transcriptomics.
• Exposure: The factor studied was a genetic alteration in the tumor: deletion of the CDKN2A gene, with or without co-deletion of a nearby cluster of IFN I genes. Asbestos was not the studied exposure. Table 1 lists asbestos exposure as Yes 77 (94.4%), No/uncertain 4 (5.6%), with 18 missing in the 89-patient cohort. No fiber types are named.
• Main results:
  • CDKN2A was deleted in 41.6% (37 of 89) of the mesotheliomas
  • CDKN2A deletion was associated with reduced survival in the study cohort (p = 0.04)
  • Deletion of the IFN I gene cluster was found in 11.2% of the whole cohort and in 27% of CDKN2A-deleted samples. The co-deletion did not further increase the survival impact of CDKN2A deletion.
  • Of 82 successfully profiled samples, 32 (39%) had the CDKN2A deletion and 50 (61%) did not
  • 373 genes differed between deleted and non-deleted tumors. 368 (98.6%) were less active in deleted tumors and 5 were more active.
  • Computational estimates from gene expression showed lower estimated abundance of immune effector cells (CD4+ and CD8+ T cells, B cells, NK cells) in deleted tumors than in non-deleted tumors
  • Both M1 and M2 macrophages were estimated to be significantly decreased in deleted tumors compared with non-deleted tumors
  • Higher expression of several of the affected chemokines and receptors was associated with improved survival in the cohort
  • In spatial analysis of 9 tumors (5 deleted, 4 not deleted), 183 genes (10.2%) differed in sarcomatoid areas, with 121 up and 62 down. Only 66 genes (3.6%) differed in epithelioid areas.
  • In sarcomatoid areas of deleted tumors, innate immune cells and B cells were estimated to be severely depleted. Mast cells and regulatory T cells showed the opposite trend and were enriched.
• The authors' conclusion: The authors concluded that in DPM, CDKN2A deletion is associated with depletion of stimulatory and chemotactic signals and exclusion of immune cells from the tumor. They concluded that this effect is prominent in sarcomatoid lesions and likely contributes to the aggressiveness associated with the deletion. They proposed testing CDKN2A deletion together with histology as a predictive criterion for immunotherapy.
• Limitations the authors state:
  • The authors noted that their findings on the IFN I cluster co-deletion may have been affected by the limited sample size and the detection method used
  • The authors stated that functional studies are still needed to clarify how the deletion reshapes the tumor environment

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: CDKN2A, Pleural Mesothelioma, checkpoint inhibitors, Sarcomatoid, Biomarker.

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• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)
• Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre — K. Marshall, S. Jackson, et al. (2020)
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