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

Sandra S. Ring, Jovana Cupovic, Lucas Onder, Mechthild Lütge, Christian Perez-Shibayama, Cristina Gil-Cruz, Elke Scandella, Angelina 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 () and Lukas Flatz ()
Additional contact information
Sandra S. Ring: Kantonsspital St.Gallen
Jovana Cupovic: Kantonsspital St.Gallen
Lucas Onder: Kantonsspital St.Gallen
Mechthild Lütge: Kantonsspital St.Gallen
Christian Perez-Shibayama: Kantonsspital St.Gallen
Cristina Gil-Cruz: Kantonsspital St.Gallen
Elke Scandella: Kantonsspital St.Gallen
Angelina Martin: Kantonsspital St.Gallen
Urs Mörbe: Kantonsspital St.Gallen
Fabienne Hartmann: Kantonsspital St.Gallen
Robert Wenger: Kantonsspital St. Gallen
Matthias Spiegl: Kantonsspital St. Gallen
Andrej Besse: Kantonsspital St.Gallen
Weldy V. Bonilla: University of Basel
Felix Stemeseder: Hookipa Pharma Inc.
Sarah Schmidt: Hookipa Pharma Inc.
Klaus K. Orlinger: Hookipa Pharma Inc.
Philippe Krebs: University of Berne
Burkhard Ludewig: Kantonsspital St.Gallen
Lukas Flatz: Kantonsspital St.Gallen

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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: 2021
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DOI: 10.1038/s41467-021-25057-w

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