Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions

Our plain-English summary of Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions, by N. Alcala, L. Mangiante, N. Le-Stang, et al (EBioMedicine, 2019).

The study

• Authors: N. Alcala, L. Mangiante, N. Le-Stang, C.E. Gustafson, S. Boyault, F. Damiola, K. Alcala, M. Brevet, F. Thivolet-Bejui, C. Blanc-Fournier, J.P. Le Rochais, G. Planchard, N. Rousseau, D. Damotte, J.C. Pairon, M.C. Copin, A. Scherpereel, E. Wasielewski, L. Wicquart, S. Lacomme, J.M. Vignaud, G. Ancelin, C. Girard, C. Sagan, C. Bonnetaud, V. Hofman, P. Hofman, J. Mouroux, V. Thomas de Montpreville, E. Clermont-Taranchon, J. Mazieres, I. Rouquette, H. Begueret, J.Y. Blay, S. Lantuejoul, R. Bueno, C. Caux, N. Girard, J.D. McKay, M. Foll, F. Galateau-Salle, L. Fernandez-Cuesta
• Journal: EBioMedicine
• Published: 2019;48:191-202
• Cited by: 64 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options.

Methods: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples.

Findings: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series.

Interpretation: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.

Copyright © 2018. Published by Elsevier B.V.

In plain English

This laboratory study analysed gene-activity data (RNA sequencing) from 284 malignant pleural mesothelioma tumours. These came from an earlier study by Bueno and colleagues (211) and from the TCGA project (73). The authors used a method that did not assume tumours fall into separate types. The tumours did not form distinct groups but spread along a continuum. One main axis was linked to blood-vessel growth (angiogenesis) genes and tracked the sarcomatoid-to-epithelioid tissue types. A second axis was linked to immune genes. In 199 samples, a survival model using both axes scored 0.70 on a prediction measure (iAUC), against 0.63 for the three tissue types and 0.67 for Bueno's four molecular groups. The authors measured five proteins in 103 of these tumours and in 77 further tumours from the French MESOBANK, and reported that the patterns and the survival link held. Asbestos exposure was not studied as a cause. It served as an adjustment variable and as one of the clinical factors tested against the molecular axes. The authors concluded that prognosis is best explained by a continuous model.

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: Laboratory molecular study: reanalysis of existing tumour RNA-sequencing data, with protein (immunohistochemistry) validation on a subset and replication in an independent series
• Who was studied: 284 malignant pleural mesothelioma tumour samples: 211 from the Bueno and colleagues study and 73 from TCGA. A subset of 103 Bueno samples was used for protein validation (106 were planned). An independent replication series of 77 samples came from the French MESOBANK. It had three groups (long-survival epithelioid, short-survival epithelioid and sarcomatoid), matched for age and sex.
• Exposure: No exposure was studied as a cause; the study examined tumour gene and protein expression. Asbestos exposure was used as a covariable in the survival models. It was also one of the clinical variables tested for association with the molecular dimensions, and the authors checked that it was balanced across the three replication groups.
• Main results:
  • Across the 284 tumours, gene-expression profiles did not form separate clusters but followed a continuum.
  • Five survival models were compared in 199 Bueno samples. Integral AUC was 0.63 for the three histopathological types, 0.62 for the percentage of sarcomatoid component, 0.67 for Bueno's four molecular groups, 0.68 for Dimension 1 alone, and 0.70 for Dimensions 1 and 2 combined.
  • In the 284-tumour analysis, samples in the top-right region had the best survival (Kaplan-Meier median 36 months). Samples on the left had the worst survival (median 10 months).
  • Dimension 1 was associated with angiogenesis genes, and Dimension 2 with immune-related gene sets.
  • Asbestos exposure was among the clinical variables tested for association with each molecular dimension by linear regression. The main text does not report the outcome of that test for asbestos; it is in supplementary Table S3.
  • In the 77-sample replication series, the authors reported that asbestos exposure was balanced between the three groups (Fisher's exact tests, p greater than 0.05), although the groups were not matched on it.
  • In the 103-sample protein validation, the positive correlations seen in gene expression were also found at the protein level: between PDL1 and CD8, and between VEGFR2 and VISTA.
  • In the 77-sample French MESOBANK replication series, the correlation structure of the five proteins matched that of the discovery series. The authors reported that the markers' prognostic value was also replicated.
  • In the replication series, VISTA was overexpressed in epithelioid subtypes usually associated with intermediate prognosis (trabecular) and bad prognosis (solid). This was despite VISTA expression being linked overall to better prognosis.
  • The authors described three profiles at the extremes of the continuum, each with an expected median survival: a 'hot' profile (7 months), a 'VEGFR2+/VISTA+' profile (36 months) and a 'cold' profile (10 months).
• The authors' conclusion: The authors concluded that the prognosis of malignant pleural mesothelioma is best explained by a continuous model, whose extremes show specific expression patterns of genes involved in angiogenesis and immune response.
• Limitations the authors state:
  • Principal Component Analysis assumes linear relationships between the summary dimensions and gene expression.
  • CD8 and VEGFR3 protein levels could only be scored in five levels rather than continuously, because the staining lacked resolution.
  • Smoking was left out of the survival models because much of the smoking information was missing.
  • The sarcomatoid group had very few samples, so one long-surviving sarcomatoid case strongly influenced the estimates.
  • Results for MKI67 and CASP3 rest only on gene-expression estimates. The authors said further studies are needed to confirm them at the protein level.

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: Pleural Mesothelioma, Asbestos Exposure, Immunohistochemistry, Prognosis, Angiogenesis.

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