Induction of potent antitumor immunity by in situ targeting of intratumoral DCs
Katsuyoshi Furumoto, … , Edgar G. Engleman, Miriam Merad
Katsuyoshi Furumoto, … , Edgar G. Engleman, Miriam Merad
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):774-783. https://doi.org/10.1172/JCI19762.
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Induction of potent antitumor immunity by in situ targeting of intratumoral DCs

Abstract

Recent reports of tumor regression following delivery of autologous tumor antigen–pulsed DCs suggest that defective antigen presentation may play a key role in tumor escape. Here we show in two different murine tumor models, CT26 (colon adenocarcinoma) and B16 (melanoma), that the number and activation state of intratumoral DCs are critical factors in the host response to tumors. We used CCL20/macrophage inflammatory protein-3α (MIP-3α) chemokine to increase the number of tumoral DCs and intratumoral injections of CG-rich motifs (CpGs) to activate such cells. Expression of CCL20 in the tumor site attracted large numbers of circulating DCs into the tumor mass and, in the case of CT26 tumors, led to complete tumor regression. Intratumoral CpG injections, in addition to CCL20, were required to induce therapeutic immunity against B16 tumors. In this model CpG overcame tumor-mediated inhibition of DC activation and enabled tumoral DCs to cross-present tumor antigens to naive CD8 T cells. CpG activation of tumoral DCs alone was not sufficient to induce tumor regression in either tumor model, nor was systemic delivery of the DC growth factor, Flt3 ligand, which dramatically increased the number of circulating DCs but not the number of tumoral DCs. These results indicate that the number of tumoral DCs as well as the tumor milieu determines the ability of tumor-bearing hosts to mount an effective antitumor immune response. Our results also suggest that DCs can be manipulated in vivo without delivery of defined tumor antigens to induce a specific T cell–mediated antitumor response and provide the basis for the use of chemokines in DC-targeted clinical strategies.

Authors

Katsuyoshi Furumoto, Luis Soares, Edgar G. Engleman, Miriam Merad

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Figure 1

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CCL20 expression in the tumor site attracts DCs into and throughout the ...
CCL20 expression in the tumor site attracts DCs into and throughout the tumor mass. Mice were inoculated with CT26 or B16 tumors transduced with CCL20 or a mock vector, and DC infiltration at the tumor site was analyzed 10–15 days later. (A) Serial frozen tumor sections were stained with anti-CD11c Ab or isotype IgG control and counterstained with hematoxylin (magnification, ×200). Frozen sections of mock-transduced (B) or CCL20-transduced B16 tumors (C) stained with anti-CD11c Ab are shown (magnification, ×200). Frozen sections of the core of a CCL20-transduced B16 tumor stained with CD11c Ab are shown at magnifications of ×400 (D) and ×600 (E). Cell suspensions of tumors (F) and tumor-draining LNs (G) were analyzed for the presence of MHC class II+ CD11c+ DCs by flow cytometry. The results shown are the mean of three separate experiments. *Statistical differences between CCL20 and mock experimental groups.