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.
View: Text | PDF
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

×

Figure 6

Enhanced antitumor immunity triggered by IL-12 is dependent on in vivo cross presentation of tumor antigens.

Options: View larger image (or click on image) Download as PowerPoint
Enhanced antitumor immunity triggered by IL-12 is dependent on in vivo c...
(A) The percentage of PI–, NK1.1–, CD3–, CD11b+, and IL-12Rβ2+ cells from single-cell suspensions of well-established B16 tumors. (B) Flow cytometric analysis with backgating for PI–CD3–B220–NK1.1–CD11b+ cells from tumors 7 days following treatment with 105 IL-12 or mock cells. (C) CD11b+ cells from B were examined for expression of H-2Db with quantification of mean fluorescence intensity for 4 independent mice (right panel). *P < 0.05, t tests compared with no treatment. All plots are representative of at least 3 independent experiments. (D) Antitumor immunity in sublethally irradiated WT, Iab–/–, or B2m–/– C57BL/6 mice bearing established B16 tumors and treated with 105 IL-12 cells. 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 IL-12 cells into B2m–/– host. (E) Representative flow cytometry plots for transferred T cells in tumors and spleens harvested from sublethally irradiated WT or B2m–/– C57BL/6 mice 7 days following the transfer of 105 IL-12–expressing pmel-1 Ly5.1+CD8+ T cells (IL-12P-Ly5.1) and 105 IL-12–expressing open-repertoire thy1.1+CD8+ T cells (IL-12OR-Thy1.1) into the same mouse. Data are representative of 3 independent samples. Numbers represent percentage of Thy1.1+Ly5.1– or Thy1.1–Ly5.1+ cells. (F) Confocal microscopy for tumor sections from mice treated in D (Thy1.1, green; CD31, red; DAPI, blue). Original magnification, ×40.