IL-12 triggers an acute-inflammatory environment within tumors that reverses dysfunctional antigen-presentation by myeloid-derived cells

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NCI	SIG/RNA/CYTOK-7

* FARE Award Winner

Authors

• S Kerkar
• R Goldszmid
• P Muranski
• D Chinnasamy
• Z Yu
• R Reger
• R Morgan
• E Wang
• F Marincola
• G Trinchieri
• S Rosenberg
• N Restifo

Abstract

Myeloid-derived cells comprising the tumor stroma represent a heterogeneous population of cells critical to the structure, function and growth of established cancers. We have recently found that engineering tumor-specific CD8+ T cells to secrete IL-12 (IL-12TD) can lead to striking improvements in T-cell activity against established melanomas in murine models. Surprisingly, IL-12-dependent enhancement of CD8+ T-cell anti-tumor function did not occur through direct ligation of receptors on lymphocytes or NK cells. Instead, IL-12 sensitized bone marrow-derived tumor-stromal cells, partly through interferon-gamma, to indirectly enhance the effects of adoptively-transferred T cells. Direct presentation of antigen by tumor was not necessary, but MHC class I expression on host cells was essential for IL-12 mediated anti-tumor enhancements. Upon successful treatment with IL-12TD cells, we observed the selective elimination of tumor-infiltrating CD11b+ F4/80Hi macrophages, CD11b+/ClassIIHi/CD11cHi dendritic cells and CD11b+/Ly6CHi/Ly6GLow but not CD11b+/Ly6CHi/Ly6GHi myeloid-derived suppressor cells within regressing lesions. These results are consistent with a model whereby IL-12 triggers the maturation of myeloid-derived cells into competent antigen cross-presenting cells. Licensed recognition of these antigens by effector T cells may in turn trigger the collapse of the tumor stroma and aid in the regression of large vascularized lesions.

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