Depletion of slow-cycling PDGFRα + ADAM12 + mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis.
Selene E Di CarloJerome RaffenneHugo VaretAnais OdeDavid Cabrerizo GranadosMerle SteinRachel LegendreJan P TuckermannCorinne BousquetLucie PedutoPublished in: Nature immunology (2023)
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.
Keyphrases
- endothelial cells
- high glucose
- poor prognosis
- prostate cancer
- induced apoptosis
- mesenchymal stem cells
- diabetic rats
- papillary thyroid
- bone marrow
- cell cycle arrest
- long non coding rna
- immune response
- high intensity
- adipose tissue
- stem cells
- squamous cell
- genome wide
- mouse model
- squamous cell carcinoma
- single cell
- radical prostatectomy
- cell proliferation
- signaling pathway
- endoplasmic reticulum stress
- gene expression
- dna methylation
- umbilical cord
- epithelial mesenchymal transition
- carbon dioxide
- electronic health record
- young adults