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IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors
Sid P. Kerkar, … , Steven A. Rosenberg, Nicholas P. Restifo
Sid P. Kerkar, … , Steven A. Rosenberg, Nicholas P. Restifo
Published November 7, 2011
Citation Information: J Clin Invest. 2011;121(12):4746-4757. https://doi.org/10.1172/JCI58814.
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Research Article Oncology Article has an altmetric score of 16

IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors

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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+F4/80hi macrophages, CD11b+MHCIIhiCD11chi dendritic cells, and CD11b+Gr-1hi 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

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Figure 7

MDSCs, macrophages, and dendritic cells residing within B16 tumors of mice treated with IL-12 cells potently stimulate the proliferation of pmel CD8+ T cells.

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MDSCs, macrophages, and dendritic cells residing within B16 tumors of mi...
(A) B16 tumors established on C57BL/6 mice for 10 days were excised 8 hours following 5-Gy TBI and examined by multicolor flow cytometry for CD45, NK1.1, TCRb, B220, CD11b, CD11c, I-Ab, F4/80, Ly6C, and Ly6G cells. Flow cytometry plot is representative of at least 3 independent samples and gated on live, NK1.1–, TCRb–, and B220– cells. Numbers represent percentage of cells within each quadrant. (B) Single-cell tumor suspensions were created 5 days following treatment of established B16 tumors with IL-12 or mock cells, and CD11b+GR1hi MDSCs, CD11b+F4/80hi macrophages, and CD11b+CD11chi dendritic cells were sorted by flow cytometry and cocultured for 72 hours with CFSE-labeled untouched pmel CD8+ T cells at a 10:1 T cells/APC ratio. Flow cytometry plots represent 3 independent samples.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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