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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CCL20 alone or in combination with CpG induces a systemic T cell–depende...
CCL20 alone or in combination with CpG induces a systemic T cell–dependent antitumor response. Mice were inoculated subcutaneously with 2 × 106 CT26 parent, CT26 mock, or CT26-CCL20–transduced tumor cells (A and B), or 5 × 104 B16 parent, B16 mock, or B16-CCL20 tumor cells in addition to intratumoral injections of CpG or ODN-CTR (C and D). Thirty days later graded numbers of spleen and LN cells were cultured in the presence of irradiated parental tumors for 5 days, and tumor-specific cytotoxic T cell activity against nontransduced parental tumor cell targets was measured using a standard 4-hour 51Cr release assay as described in Methods (A and C). Results shown are representative of two separate experiments. (B) Mice were injected intraperitoneally with depleting anti-CD8, anti-CD4, or control rat Ab’s to deplete circulating T cells, or anti–asialo-GM1 serum, or control rabbit serum for NK cell depletion. *P < 0.05 between CCL20/control IgG and CCL20/CD4 Ab– and CCL20/CD8 Ab–treated groups. (D) CD4–/–, CD8–/–, or WT mice were inoculated with B16-CCL20 tumor cells followed by intratumoral CpG injections. NK cell depletion was done as in B. *P < 0.05 between WT mice and CD8–/– mice treated with CCL20 + CpG. There was no significant difference in tumor growth between WT mice and CD4–/– mice treated with CCL20 + CpG.