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