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Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment

Athanasios Papadas1, Gauri Deb2, Alexander Cicala2

  • 1Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.

Cell Reports
|August 17, 2022
PubMed

Insights

Stromal remodeling in tumors guides immune cells. Proteolytic fragments of versican (VCAN) promote accumulation and activation of conventional type 1 dendritic cells (cDC1s), enhancing anti-tumor immunity.

Area of Science:

  • Tumor microenvironment immunology
  • Dendritic cell biology
  • Extracellular matrix remodeling

Background:

  • Type 1 conventional dendritic cells (cDC1s) interact with CD8+ T cells at tumor boundaries.
  • The accumulation of cDC1s in tumor stroma suggests active regulation beyond passive exclusion.
  • Embryonic morphogenesis involves stromal remodeling and cell fate cue generation.

Purpose of the Study:

  • To investigate the role of invasive margin stromal remodeling in regulating cDC1 behavior.
  • To understand how stromal modifications influence cDC1 abundance and function in T cell-inflamed tumors.

Main Methods:

  • Analysis of cDC1 and CD8+ T cell distribution in human tumors.
  • Investigation of versican (VCAN) proteolysis and its role in cDC1 accumulation.
  • Assessment of versikine's effect on cDC1 differentiation and activation, including DNA sensing pathways.

Main Results:

  • CD8+ T cells infiltrate tumor nests, while cDC1s are restricted to adjacent stroma.
  • Site-specific proteolysis of versican (VCAN) is observed in the tumor stroma.
  • VCAN is essential for cDC1 accumulation, and its fragment versikine is sufficient.
  • Versikine orchestrates cDC1 activation, enhancing DNA sensing sensitivity, independent of pre-DC differentiation.
  • Atypical innate lymphoid cells support versikine-mediated cDC1 activation.

Conclusions:

  • Peritumoral stromal remodeling, mimicking embryonic provisional matrix, regulates cDC1 abundance and activity.
  • Versican proteolysis and its matrikine versikine are key regulators of cDC1 behavior in the tumor microenvironment.
  • This stromal regulation contributes to the development of T cell-inflamed tumors.

Keywords:
CD40CP: CancerCP: ImmunologycDC1checkpoint inhibitorsdendritic cellsimmunotherapyproteoglycanstumor matrixtumor stromaversicanversikine

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