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

Sid P. Kerkar, Anthony J. Leonardi, Nicholas J. Van Panhuys, Ling Zhang, Zhiya Yu, Joseph G. Crompton, Jenny H. Pan, Douglas C. Palmer, Richard A. Morgan, Steven A. Rosenberg, Nicholas P. Restifo

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Abstract

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.

Original languageEnglish
Pages (from-to)1369-1377
Number of pages9
JournalMolecular Therapy
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Kerkar, S. P., Leonardi, A. J., Van Panhuys, N. J., Zhang, L., Yu, Z., Crompton, J. G., Pan, J. H., Palmer, D. C., Morgan, R. A., Rosenberg, S. A., & Restifo, N. P. (2013). Collapse of the tumor stroma is triggered by IL-12 induction of Fas. Molecular Therapy, 21(7), 1369-1377. https://doi.org/10.1038/mt.2013.58