The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities - CEA - Université Paris-Saclay Accéder directement au contenu
Article Dans Une Revue Theranostics Année : 2020

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

Masahiko Nishiyama
  • Fonction : Auteur

Résumé

Purpose: Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has already been the object of several studies, however little is known regarding the functional genomics and the tumor microenvironment despite their importance in oncology. Our investigation aimed at describing both the functional genomics of SDC and the SDC microenvironment, along with their clinical relevance. Methods: RNA-sequencing (24 tumors), proteomics (17 tumors), immunohistochemistry (22 tumors), and multiplexed immunofluorescence (3 tumors) data were obtained from three different patient cohorts and analyzed by digital imaging and bioinformatics. Adjacent non-tumoral tissue from patients in two cohorts were used in transcriptomic and proteomic analyses. Results: Transcriptomic and proteomic data revealed the importance of Notch, TGF-β, and interferon-γ signaling for all SDCs. We confirmed an overall strong desmoplastic reaction by measuring α-SMA abundance, the level of which was associated with recurrence-free survival (RFS). Two distinct immune phenotypes were observed: immune-poor SDCs (36%) and immune-infiltrated SDCs (64%). Advanced bioinformatics analysis of the transcriptomic data suggested 72 ligand-receptor interactions occurred in the microenvironment and correlated with the immune phenotype. Among these interactions, three immune checkpoints were validated by immunofluorescence, including CTLA-4/DC86 and TIM-3/galectin-9 interactions, previously unidentified in SDC. Immunofluorescence analysis also confirmed an important immunosuppressive role of macrophages and NK cells, also supported by the transcriptomic data. Conclusions: Together our data significantly increase the understanding of SDC biology and open new perspectives for SDC tumor treatment. Before applying immunotherapy, patient stratification according to the immune infiltrate should be taken into account. Immune-infiltrated SDC could benefit from immune checkpoint-targeting therapy, with novel options such as anti-CTLA-4. Macrophages or NK cells could also be targeted. The dense stroma, i.e., fibroblasts or hyaluronic acid, may also be the focus for immune-poor SDC therapies, e.g. in combination with Notch or TGF-β inhibitors, or molecules targeting SDC mutations.
Fichier principal
Vignette du fichier
v10p4383.pdf (2.27 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03524961 , version 1 (13-01-2022)

Licence

Paternité

Identifiants

Citer

Melissa Alame, Emmanuel Cornillot, Valère Cacheux, Guillaume Tosato, Marion Four, et al.. The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities. Theranostics, 2020, 10 (10), pp.4383-4394. ⟨10.7150/thno.42986⟩. ⟨hal-03524961⟩
25 Consultations
32 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More