Collapse of the tumor stroma is triggered by IL-12 induction of Fas

Mol Ther. 2013 Jul;21(7):1369-77. doi: 10.1038/mt.2013.58. Epub 2013 Apr 9.


Engineering CD8⁺ T cells to deliver interleukin 12 (IL-12) to the tumor site can lead to striking improvements in the ability of adoptively transferred T cells to induce the regression of established murine cancers. We have recently shown that IL-12 triggers an acute inflammatory environment that reverses dysfunctional antigen presentation by myeloid-derived cells within tumors and leads to an increase in the infiltration of adoptively transferred antigen-specific CD8⁺ T cells. Here, we find that local delivery of IL-12 increased the expression of Fas within tumor-infiltrating macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSC), and that these changes were abrogated in mice deficient in IL-12-receptor signaling. Importantly, upregulation of Fas in host mice played a critical role in the proliferation and antitumor activity of adoptively transferred IL-12-modified CD8⁺ T cells. We also observed higher percentages of myeloid-derived cell populations within tumors in Fas-deficient mice, indicating that tumor stromal destruction was dependent on the Fas death receptor. Taken together, these results describe the likely requirement for costimulatory reverse signaling through Fasl on T cells that successfully infiltrate tumors, a mechanism triggered by the induction of Fas expression on myeloid-derived cells by IL-12 and the subsequent collapse of the tumor stroma.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Dendritic Cells / metabolism
  • Female
  • Flow Cytometry
  • Interleukin-12 / administration & dosage
  • Interleukin-12 / therapeutic use*
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • fas Receptor / genetics
  • fas Receptor / metabolism*


  • fas Receptor
  • Interleukin-12