EBioMedicine (Oct 2019)

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactionsResearch in context

  • Nicolas Alcala,
  • Lise Mangiante,
  • Nolwenn Le-Stang,
  • Corinne E. Gustafson,
  • Sandrine Boyault,
  • Francesca Damiola,
  • Karine Alcala,
  • Marie Brevet,
  • Françoise Thivolet-Bejui,
  • Cécile Blanc-Fournier,
  • Jean-Philippe Le Rochais,
  • Gaëtane Planchard,
  • Nathalie Rousseau,
  • Diane Damotte,
  • Jean Claude Pairon,
  • Marie Christine Copin,
  • Arnaud Scherpereel,
  • Eric Wasielewski,
  • Laurence Wicquart,
  • Stéphanie Lacomme,
  • Jean-Michel Vignaud,
  • Gaspard Ancelin,
  • Cécile Girard,
  • Christine Sagan,
  • Christelle Bonnetaud,
  • Véronique Hofman,
  • Paul Hofman,
  • Jérôme Mouroux,
  • Vincent Thomas de Montpreville,
  • Estelle Clermont-Taranchon,
  • Julien Mazieres,
  • Isabelle Rouquette,
  • Hugues Begueret,
  • Jean-Yves Blay,
  • Sylvie Lantuejoul,
  • Raphael Bueno,
  • Christophe Caux,
  • Nicolas Girard,
  • James D. McKay,
  • Matthieu Foll,
  • Françoise Galateau-Salle,
  • Lynnette Fernandez-Cuesta

Journal volume & issue
Vol. 48
pp. 191 – 202

Abstract

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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. Keywords: Pleural mesothelioma, Immunotherapy, Angiogenesis, MESOMICS project, French MESOBANK