Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy

Our plain-English summary of Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy, by F. Torricelli, B. Donati, F. Reggiani, et al (Molecular Cancer, 2023).

The study

• Authors: F. Torricelli, B. Donati, F. Reggiani, V. Manicardi, S. Piana, R. Valli, F. Lococo, A. Ciarrocchi
• Journal: Molecular Cancer
• Published: 2023;22(1):114
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients' management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place.

Methods: We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis.

Results: Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability.

Conclusions: Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease.

© 2023. The Author(s).

In plain English

This laboratory study examined biphasic malignant pleural mesothelioma, which contains both epithelioid and sarcomatoid cells, to study how one cell type changes into the other. Using stored tumor tissue from patients seen between 2010 and 2019, the authors measured the activity of 1834 genes in mapped areas of 8 biphasic tumors. They then checked selected genes in a separate group of 84 mesotheliomas. In the 8 tumors, 355 genes were more active in epithelioid areas and 263 in sarcomatoid areas, and 55% of the latter were involved in inflammation and immune cells. Sarcomatoid areas also showed more signs of immune cells such as macrophages, and higher levels of immune checkpoint genes. Activity of the gene TGFB1 was positively correlated with macrophage markers. In the 84-tumor group, patients in the highest quarter of TGFB1 levels had significantly shorter survival than those in the lowest quarter, also after accounting for tumor type. Patients' asbestos exposure was not reported. The authors called the work descriptive and exploratory and said it may have clinical implications, including for immunotherapy.

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: Retrospective laboratory study using spatial (location-mapped) gene expression profiling of tumor tissue, with validation by a separate gene-panel analysis and survival analysis
• Who was studied: Consecutive malignant pleural mesothelioma patients from the authors' institution's Pathology Unit, 2010 to 2019. The training set was 8 biphasic tumors (8 pure epithelioid areas, 11 pure sarcomatoid areas, and 60 transitional areas, each split into epithelioid and sarcomatoid parts). The validation set was 84 tumors (34 epithelioid, 32 biphasic, 18 sarcomatoid); 27 further samples were excluded for poor RNA quality.
• Exposure: No asbestos exposure was measured or reported for these patients. The study measured gene activity (RNA) in tumor tissue: 1834 genes in the spatial analysis and a 217-gene panel in the validation set.
• Main results:
  • In the 8 biphasic tumors, 618 genes differed significantly between epithelioid and sarcomatoid areas: 355 were higher in epithelioid areas and 263 were higher in sarcomatoid areas.
  • 55% of genes more active in sarcomatoid areas were involved in inflammation and immune cell modulation.
  • Gene-based estimates showed macrophages, neutrophils and monocytes significantly more represented in sarcomatoid than epithelioid areas.
  • Several immune checkpoint genes (including HAVCR2, LGALS9 and CD86) were significantly higher in sarcomatoid areas than in epithelioid areas.
  • Across the mapped areas, TGFB1 was positively correlated with macrophage markers. The highest correlation was with CD68 (R = 0.7, p = 2.2e-16); CD163 had R = 0.47 and MRC1 had R = 0.39.
  • In the 84-tumor validation cohort, comparing patients in the first (lowest) and fourth (highest) quartiles of TGFB1 expression, TGFB1 expression was significantly correlated with reduced survival probability. No hazard ratio is given in the text.
  • TGFB1 remained associated with worse prognosis in a multivariate analysis that included histological type.
• The authors' conclusion: The authors concluded that, although exploratory, their data may have clinical implications, including TGFB1 as a possible prognostic marker. They also said the data may help explain responses to immune checkpoint inhibitors and guide strategies to use these drugs in mesothelioma.
• Limitations the authors state:
  • The authors stated that this is a descriptive study limited to gene transcripts.
  • The authors described the data as still exploratory.

Topics

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

Medical terms in this study, explained in our Lexicon: Biphasic Mesothelioma, Pleural Mesothelioma, Immunotherapy, Epithelioid, Pleomorphic, Sarcomatoid, Life Expectancy, Macrophage.

Related studies

• Survival results in biphasic malignant pleural mesothelioma patients: A multicentric analysis — F. Lococo, F. Torricelli, et al. (2020)
• Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort — S. Brosseau, C. Danel, et al. (2019)
• A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials — V.C. Sanchez, P. Weston, et al. (2011)
• 3-Dimensional Quantification of Composite Pleural Plaque Volume in Patients Exposed to Asbestos Using High-resolution Computed Tomography: A Validation Study — G. Dournes, A. Dubois, et al. (2019)
• Bringing together evolution on serpentine and polyploidy: spatiotemporal history of the diploid-tetraploid complex of Knautia arvensis (Dipsacaceae) — F. Kolář, T. Fér, et al. (2012)
• Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial — S.I. Katz, L. Roshkovan, et al. (2021)

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