Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nature Immunology Année : 2023

Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis

Résumé

The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12+PDGFRα+ mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12+ MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3 and Csf1. Genetic depletion of ADAM12+ cells restored a functional tumor vasculature, reduced hypoxia and acidosis and normalized CAFs, inducing infiltration of effector T cells and growth inhibition of melanomas and pancreatic neuroendocrine cancer, in a process dependent on TGF-β. In human cancer, ADAM12 stratifies patients with high levels of hypoxia and innate resistance mechanisms, as well as factors associated with a poor prognosis and drug resistance such as AXL. Altogether, our data show that depletion of tumor-induced slow-cycling PDGFRα+ MSCs through ADAM12 restores antitumor immunity.
Fichier principal
Vignette du fichier
s41590-023-01642-7.pdf (14.36 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

pasteur-04230561 , version 1 (06-10-2023)

Licence

Paternité

Identifiants

Citer

Selene E Di Carlo, Jerome Raffenne, Hugo Varet, Anais Ode, David Cabrerizo Granados, et al.. Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis. Nature Immunology, In press, Online ahead of print. ⟨10.1038/s41590-023-01642-7⟩. ⟨pasteur-04230561⟩
18 Consultations
8 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More