Plasmacytoid dendritic cells induce NK cell–dependent, tumor antigen–specific T cell cross-priming and tumor regression in mice
Chengwen Liu, … , Gang Wang, Patrick Hwu
Chengwen Liu, … , Gang Wang, Patrick Hwu
Published February 7, 2008
Citation Information: J Clin Invest. 2008;118(3):1165-1175. https://doi.org/10.1172/JCI33583.
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Research Article Oncology

Plasmacytoid dendritic cells induce NK cell–dependent, tumor antigen–specific T cell cross-priming and tumor regression in mice

Abstract

A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL cross-priming against multiple B16 tumor antigens, leading to the regression of both treated tumors and untreated tumors at distant contralateral sites. This T cell cross-priming was mediated by conventional DCs (cDCs) and was completely dependent upon the early recruitment and activation of NK cells at the tumor site. NK cell recruitment was mediated by CCR5 via chemokines secreted by pDCs, and optimal IFN-γ production by NK cells was mediated by OX40L expressed by pDCs. Our data thus demonstrated that activated pDCs are capable of initiating effective and systemic antitumor immunity through the orchestration of an immune cascade involving the sequential activation of NK cells, cDCs, and CD8+ T cells.

Authors

Chengwen Liu, Yanyan Lou, Gregory Lizée, Hong Qin, Shujuan Liu, Brian Rabinovich, Grace J. Kim, Yi-Hong Wang, Yang Ye, Andrew G. Sikora, Willem W. Overwijk, Yong-Jun Liu, Gang Wang, Patrick Hwu

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Figure 1

Activated pDC administration induces systemic antitumor activity requiring CD8+ T cells.

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Activated pDC administration induces systemic antitumor activity requiri...
Mice bearing 7-day, established subcutaneous B16 tumors were treated by i.t. injection with CpG-activated pDCs, resting pDCs, or saline. Depicted are (A) tumor growth (*P = 0.043 for pDC/CpG versus pDC) and (B) mouse survival as monitored over time following treatment (**P = 0.02 for pDC/CpG versus pDC). (C) Mice bearing subcutaneous B16 tumors in both flanks were treated by i.t. pDC injection in only 1 tumor. Graph depicts growth of untreated, contralateral tumors over time following treatment with CpG-activated or resting pDCs (#P = 0.021 for pDC/CpG versus pDC). (D) Mice bearing single subcutaneous B16 tumors were treated as described in the setting of Ab-mediated CD4+ T cell or CD8+ T cell depletion. Graph depicts tumor growth over time following treatment (##P = 0.009 for pDC/CpG versus pDC/CpG with CD8 depletion). Data shown are expressed as mean ± SEM and are representative of 2 to 3 independent experiments with similar results.