TY - JOUR
T1 - Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells
AU - Ortiz, Myrna L.
AU - Kumar, Vinit
AU - Martner, Anna
AU - Mony, Sridevi
AU - Donthireddy, Laxminarasimha
AU - Condamine, Thomas
AU - Seykora, John
AU - Knight, Stella C.
AU - Malietzis, George
AU - Lee, Gui Han
AU - Moorghen, Morgan
AU - Lenox, Brianna
AU - Luetteke, Noreen
AU - Celis, Esteban
AU - Gabrilovich, Dmitry
N1 - Publisher Copyright:
© 2015 Ortiz et al.
PY - 2015/3/9
Y1 - 2015/3/9
N2 - Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33+S100A9+ cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4+ T cells. This chemokine was released by activated IMCs. Elimination of CD4+ T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4+ T cells.
AB - Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33+S100A9+ cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4+ T cells. This chemokine was released by activated IMCs. Elimination of CD4+ T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4+ T cells.
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U2 - 10.1084/jem.20140835
DO - 10.1084/jem.20140835
M3 - Article
C2 - 25667306
AN - SCOPUS:84924662639
SN - 0022-1007
VL - 212
SP - 351
EP - 367
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -