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

Nat Commun. 2021 Aug 5;12(1):4734. doi: 10.1038/s41467-021-25057-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology
  • Cancer-Associated Fibroblasts / immunology
  • Cancer-Associated Fibroblasts / pathology
  • Cellular Reprogramming Techniques / methods
  • Chemokine CXCL13 / genetics
  • Chemokine CXCL13 / immunology
  • Female
  • Genetic Vectors
  • Interleukin-33 / deficiency
  • Interleukin-33 / genetics
  • Interleukin-33 / immunology
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / immunology
  • Lymphocytic choriomeningitis virus / genetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Stromal Cells / immunology
  • Stromal Cells / pathology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Microenvironment / immunology


  • Antigens, Neoplasm
  • Cancer Vaccines
  • Chemokine CXCL13
  • Cxcl13 protein, mouse
  • Il33 protein, mouse
  • Interleukin-33
  • Intramolecular Oxidoreductases
  • dopachrome isomerase