Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment.

DOI
Publisher DOI
PubMed ID
34354077
Abstract
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.
Date Issued
2021-08-05
Publication Type
Article
Subject(s)
Language(s)
en
Author(s)
Ring, Sandra S
Cupovic, Jovana
Onder, Lucas
Lütge, Mechthild
Perez-Shibayama, Christian
Gil-Cruz, Cristina
Scandella, Elke
De Martin, Angelina
Mörbe, Urs
Hartmann, Fabienne
Wenger, Robert
Spiegl, Matthias
Besse, Andrej
Bonilla, Weldy V
Stemeseder, Felix
Schmidt, Sarah
Orlinger, Klaus K
Ludewig, Burkhard
Flatz, Lukas
Additional Credits
Journal
Nature communications
Publisher
Nature Publishing Group
ISSN
2041-1723
Access(Rights)
open.access
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