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

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 4

IL-12–induced sensitization of endogenous immunity is independent of host T, B, and NK cells, but increases tumor infiltration of adoptively transferred T cells.

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IL-12–induced sensitization of endogenous immunity is independent of hos...
(A) Antitumor immunity following the transfer of 105 IL-12 cells into sublethally irradiated WT or Rag1–/– C57BL/6 mice (n = 5) bearing subcutaneous B16 tumors established for 10 days. (B) Tumor treatment of 105 IL-12 cells adoptively transferred into sublethally irradiated tumor-bearing WT or Rag1–/– C57BL/6 mice depleted of NK cells. All data in A and B 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. (C) Representative flow cytometry plots (left panel) and enumeration (right panel) of adoptively transferred T cells (CD8+ thy1.1+) from single-cell tumor suspensions 3 and 7 days following treatment with 105 IL-12 or mock cells in NK-depleted Rag1–/– mice. Data are expressed as mean ± SEM, *P < 0.05, Student t test. All flow cytometry plots gated on live PI– cells and numbers represent percentage of CD8+ Thy1.1+ cells. (D) Tumor sections from sublethally irradiated WT mice 7 days following the treatment of 105 IL-12 or mock cells were stained for thy1.1 on transferred T cells (green), CD31 expressed on endothelial cells (red), and DAPI (blue) to stain the nucleus. Stained sections were analyzed using fluorescence confocal microscopy. Original magnification, ×40.