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

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

Research output: Contribution to journalArticle

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 hiCD11c 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-&γαμμα;. 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.

Original languageEnglish (US)
Pages (from-to)4746-4757
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number12
DOIs
StatePublished - Dec 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Kerkar, S. P., Goldszmid, R. S., Muranski, P., Chinnasamy, D., Yu, Z., Reger, R. N., Leonardi, A. J., Morgan, R. A., Wang, E., Marincola, F. M., Trinchieri, G., Rosenberg, S. A., & Restifo, N. P. (2011). IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. Journal of Clinical Investigation, 121(12), 4746-4757. https://doi.org/10.1172/JCI58814