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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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+F4/80hi 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 1

Antitumor immunity of IL-12–engineered pmel-1 CD8+ T cells (IL-12 cells) is not dependent on type I self polarization but does require an endogenous response to secreted IL-12.

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Antitumor immunity of IL-12–engineered pmel-1 CD8+ T cells (IL-12 cells)...
(A) Representative intracellular flow cytometry plot for IL-12 expression in WT or Il12rb2–/– CD8+ cells. (B) Representative histogram for CD62L, IL-2Rα, IL-7Rα, and Sca-1 expression in WT or Il12rb2–/– IL-12 cells. (C) Intracellular staining for IFN-γ and TNF-α in WT or Il12rb2–/– IL-12 cells stimulated with PMA/ionomycin. All flow cytometry data in A–C are representative of at least 3 independent experiments. Numbers represent percentage of cells in each quadrant. (D) Tumor treatment with 105 WT or Il12rb2–/– IL-12 cells transferred into sublethally irradiated (5-Gy TBI) C57BL/6 mice bearing 10-day established subcutaneous B16 tumors (n = 5). All data are expressed as mean ± SEM and are representative of 2 independent experiments. *P < 0.05, Wilcoxon’s rank-sum test compared with no treatment (NT) control. (E) Antitumor immunity of 105 WT IL-12 cells transferred into sublethally irradiated WT or Il12rb2–/– C57BL/6 mice bearing subcutaneous B16 tumors established for 10 days. All data are expressed as mean ± SEM and are representative of 2 independent experiments. *P < 0.05, Wilcoxon’s rank-sum test compared with no treatment control; ΨP < 0.05, compared with WT IL-12 cells in Il12rb2–/– host.