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

Sandra Ring, Jovana Cupovic, Lucas Onder, Mechthild Lütge, Christian Perez Shibayama, Cristina Gil Cruz, Elke Scandella, Angelina De Martin, Urs Mörbe, Fabienne Hartmann, Robert Wenger, Matthias Spiegl, Andrej Besse, Weldy V Bonilla, Felix Stemeseder, Sarah Schmidt, Klaus K Orlinger, Philippe Krebs, Burkhard Ludewig & Lukas Flatz

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.
   
citation Ring S, Cupovic J, Onder L, Lütge M, Perez Shibayama C, Gil Cruz C, Scandella E, De Martin A, Mörbe U, Hartmann F, Wenger R, Spiegl M, Besse A, Bonilla W V, Stemeseder F, Schmidt S, Orlinger K K, Krebs P, Ludewig B, Flatz L. Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment. Nat Commun 2021; 12:4734.
   
type journal paper/review (English)
date of publishing 05-08-2021
journal title Nat Commun (12/1)
ISSN electronic 2041-1723
pages 4734
PubMed 34354077
DOI 10.1038/s41467-021-25057-w