Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment.
Animals
Antigens, Neoplasm
/ genetics
Cancer Vaccines
/ genetics
Cancer-Associated Fibroblasts
/ immunology
Cellular Reprogramming Techniques
/ methods
Chemokine CXCL13
/ genetics
Female
Genetic Vectors
Interleukin-33
/ deficiency
Intramolecular Oxidoreductases
/ genetics
Lymphocytic choriomeningitis virus
/ genetics
Melanoma, Experimental
/ immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Stromal Cells
/ immunology
T-Lymphocytes
/ immunology
Tumor Microenvironment
/ immunology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 08 2021
05 08 2021
Historique:
received:
09
12
2020
accepted:
19
07
2021
entrez:
6
8
2021
pubmed:
7
8
2021
medline:
14
8
2021
Statut:
epublish
Résumé
The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.
Identifiants
pubmed: 34354077
doi: 10.1038/s41467-021-25057-w
pii: 10.1038/s41467-021-25057-w
pmc: PMC8342618
doi:
Substances chimiques
Antigens, Neoplasm
0
Cancer Vaccines
0
Chemokine CXCL13
0
Cxcl13 protein, mouse
0
Il33 protein, mouse
0
Interleukin-33
0
Intramolecular Oxidoreductases
EC 5.3.-
dopachrome isomerase
EC 5.3.3.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4734Informations de copyright
© 2021. The Author(s).
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