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: Sid P Kerkar, Romina S Goldszmid, Pawel Muranski, Dhanalakshmi Chinnasamy, Zhiya Yu, Robert N Reger, Anthony J Leonardi, Richard A Morgan, Ena Wang, Francesco M Marincola, Giorgio Trinchieri, Steven A Rosenberg, Nicholas P Restifo
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 12 Pg. 4746-57 (Dec 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 22056381 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antigens, Neoplasm
• Neoplasm Proteins
• Recombinant Fusion Proteins
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• Antigen Presentation
• Antigen-Presenting Cells (immunology, pathology)
• Antigens, Neoplasm (immunology)
• Bone Marrow Cells (immunology, pathology)
• CD8-Positive T-Lymphocytes (metabolism, transplantation)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Immunotherapy, Adoptive
• Inflammation (genetics)
• Interferon-gamma (physiology)
• Interleukin-12 (genetics, metabolism, physiology)
• Lymphocyte Subsets (immunology, pathology)
• Macrophages (physiology)
• Melanoma, Experimental (immunology, pathology, therapy)
• Mice
• Myeloid Cells (physiology)
• Neoplasm Proteins (biosynthesis, genetics, immunology)
• Radiation Chimera
• Recombinant Fusion Proteins (physiology)
• Stromal Cells (pathology, physiology)
• Tumor Escape (immunology)
• Tumor Microenvironment (immunology)