Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokinesReport as inadecuate

Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines - Download this document for free, or read online. Document in PDF available to download.

Journal of Translational Medicine

, 5:56

First Online: 14 November 2007Received: 16 September 2007Accepted: 14 November 2007DOI: 10.1186-1479-5876-5-56

Cite this article as: Winter, H., van den Engel, N.K., Rüttinger, D. et al. J Transl Med 2007 5: 56. doi:10.1186-1479-5876-5-56


BackgroundThe mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 D5 melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site.

MethodsThese studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes TVDLN, were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-γ or TNF-α was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide NO was determined using GRIES reagent.

ResultsWe observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1α and MIP-1β following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-γ or TNF-α, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant KC, MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin-deficient PKO effector T cells induced macrophages to secrete nitric oxide NO, providing an additional effector mechanism for T cell-mediated tumor regression.

ConclusionThese data suggest two possible sources for chemokine secretion that stimulates macrophage recruitment to the site of tumor metastases. Both appear to be initiated by T cell recognition of specific antigen, but one is dependent on the tumor cells to produce the chemokines that recruit macrophages.

AbbreviationsCMComplete medium

MIP 1α-CCL3macrophage inflammatory protein-1 alpha

MIP 1β-CCL4macrophage inflammatory protein-1 beta

MCP-1-CCL2monocyte chemoattractant protein

RANTES-CCL5regulated on activation, normal T cell expressed and secreted

IP-10-CXCL10interferon gamma inducible protein 10

MIG-CXCL9monokine induced by interferon-gamma

KCkeratinocyte-derived chemokine

PKOperforin knock-out mouse

PTxpertussis toxin

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-5-56 contains supplementary material, which is available to authorized users.

Hauke Winter, Natasja K van den Engel contributed equally to this work.

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Author: Hauke Winter - Natasja K van den Engel - Dominik Rüttinger - Jürgen Schmidt - Matthias Schiller - Christian H Poehlein -


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