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

Alcala, Nicolas; Mangiante, Lise; Stang, Nolwenn Le; Gustafson, Corinne E.; Boyault, Sandrine; Damiola, Francesca; Alcala, Karine; Brevet, Marie; Thivolet‐Béjui, F.; Blanc-Fournier, Cécile; Rochais, Jean-Philippe Le; Planchard, G.; Rousseau, Nathalie; Damotte, Diane; Pairon, J.-C.; Copin, Marie Christine; Scherpereel, Arnaud; Wasielewski, E.; Wicquart, Laurence; Lacomme, Stéphanie; Vignaud, Jean-Michel; Ancelin, Gaspard; Girard, Cécile; Sagan, Christine; Bonnetaud, Christelle; Hofman, Véronique; Hofman, Paul; Mouroux, Jérôme; Montpréville, Vincent Thomas de; Clermont‐Taranchon, Estelle; Mazières, Julien; Rouquette, Isabelle; Bégueret, Hugues; Blay, Jean‐Yves; Lantuéjoul, Sylvie; Bueno, Raphael; Caux, Christophe; Girard, Nicolas; McKay, James; Foll, Matthieu; Galateau-Salle, Françoise; Fernández-Cuesta, Lynnette

doi:10.1016/j.ebiom.2019.09.003

Cited by 58 publications

(73 citation statements)

References 41 publications

(70 reference statements)

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“…They also have a strong prognostic value and may be of interest for guiding therapeutic strategies (38,39). Another recent publication further sustained that MPM heterogeneity is better described by a continuum (40).…”

Section: Mesothelioma Heterogeneitymentioning

confidence: 97%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra-and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

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Section: Mesothelioma Heterogeneitymentioning

confidence: 97%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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“…These E/S.scores are highly associated with the prognosis and may have an impact on personalized therapeutic strategies in MPM, particularly targeted therapies and immunotherapies (Blum et al , 2019). A recent publication has also shown that MPM heterogeneity is well described by a continuum (Alcala et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival

et al. 2020

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“… 33–37 These studies use different techniques such as Nanostring technology, 34 mass cytometry, 33 or RNA-sequencing. 36 The diversity of obtained results suggests that the composition and role of the tumor microenvironment in MPM is remarkably complex and controversial, and thus further studies will contribute to elucidate this question.…”

Section: Discussionmentioning

confidence: 99%

Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification

Alay

Cordero

Hijazo-Pechero

et al. 2021

J Immunother Cancer

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BackgroundMalignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lung mesothelium. Immune checkpoint inhibitors (ICI) in MPM have not been extremely successful, likely due to poor identification of suitable candidate patients for the therapy. We aimed to identify cellular immune fractions associated with clinical outcome and classify patients with MPM based on their immune contexture. For each defined group, we sought for molecular specificities that could help further define our MPM classification at the genomic and transcriptomic level, as well as identify differential therapeutic strategies based on transcriptional signatures predictive of drug response.MethodsThe abundance of 20 immune cell fractions in 516 MPM samples from 7 gene expression datasets was inferred using gene set variation analysis. Identification of clinically relevant fractions was performed with Cox proportional-hazards models adjusted for age, stage, sex, and tumor histology. Immune-based groups were defined based on the identified fractions.ResultsT-helper 2 (TH2) and cytotoxic T (TC) cells were found to be consistently associated with overall survival. Three immune clusters (IG) were subsequently defined based on TH2 and TC immune infiltration levels: IG1 (54.5%) was characterized by high TH2 and low TC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. While no differential genomic alterations were identified among immune groups, at the transcriptional level, IG1 samples showed upregulation of proliferation signatures, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, the integration of gene expression with functional signatures of drug response showed that IG3 patients might be more likely to respond to ICI.ConclusionsThis study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of patients with MPM with better prognosis and who might benefit from immune-based therapies. Molecular specificities of the different groups might be used to tailor specific potential therapies in the future.

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

Cited by 58 publications

References 41 publications

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival

Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification

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