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

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; Krebs, Philippe; Ludewig, Burkhard and Flatz, Lukas (2021). Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment. Nature communications, 12(1), p. 4734. Nature Publishing Group 10.1038/s41467-021-25057-w

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Krebs, Philippe

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Philippe Krebs

Date Deposited:

27 Aug 2021 08:56

Last Modified:

29 Aug 2021 03:07

Publisher DOI:

10.1038/s41467-021-25057-w

PubMed ID:

34354077

BORIS DOI:

10.48350/157989

URI:

https://boris.unibe.ch/id/eprint/157989

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