title: IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.
abstract: Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marrow-derived tumor stromal cells, including CD11b(+)F4/80(hi) macrophages, CD11b(+)MHCII(hi)CD11c(hi) dendritic cells, and CD11b(+)Gr-1(hi) myeloid-derived suppressor cells, causing them to enhance the effects of adoptively transferred CD8(+) T cells. This reprogramming of myeloid-derived cells occurred partly through IFN-γ. Surprisingly, direct presentation of antigen to the transferred CD8(+) T cells by tumor was not necessary; however, MHCI expression on host cells was essential for IL-12-mediated antitumor enhancements. These results are consistent with a model in which IL-12 enhances the ability of CD8(+) T cells to collapse large vascularized tumors by triggering programmatic changes in otherwise suppressive antigen-presenting cells within tumors and support the use of IL-12 as part of immunotherapy for the treatment of solid tumors.
authors: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1502, USA. kerkars@mail.nih.gov
authors: Sid P
authors: SP
authors: Kerkar
authors: Romina S
authors: RS
authors: Goldszmid
authors: Pawel
authors: P
authors: Muranski
authors: Dhanalakshmi
authors: D
authors: Chinnasamy
authors: Zhiya
authors: Z
authors: Yu
authors: Robert N
authors: RN
authors: Reger
authors: Anthony J
authors: AJ
authors: Leonardi
authors: Richard A
authors: RA
authors: Morgan
authors: Ena
authors: E
authors: Wang
authors: Francesco M
authors: FM
authors: Marincola
authors: Giorgio
authors: G
authors: Trinchieri
authors: Steven A
authors: SA
authors: Rosenberg
authors: Nicholas P
authors: NP
authors: Restifo
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D000951:Antigens, Neoplasm / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000637:transplantation*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007249:Inflammation / Q000235:genetics; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D022423:Myeloid Cells / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017154:Stromal Cells / Q000473:pathology / Q000502:physiology; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D007371:Interferon-gamma