title: Collapse of the tumor stroma is triggered by IL-12 induction of Fas.
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.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sid P
authors.initials: SP
authors.lastname: Kerkar
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Leonardi
authors.forename: Nicolas
authors.initials: N
authors.lastname: van Panhuys
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Pan
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D019014:fas Receptor; D018664:Interleukin-12