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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Intratumoral CCL20 alone or in combination with CpG induces the regressi...
Intratumoral CCL20 alone or in combination with CpG induces the regression of preexisting parental tumors. (A and B) Mice were inoculated subcutaneously with 2 × 106 CT26 parental (A) or 5 × 104 B16 parental tumor cells (B). Five days later the mice were injected in the opposite flank with CT26 mock or CT26-CCL20–transduced tumor cells (A) or B16 mock or B16-CCL20–transduced tumor cells in addition to two intratumoral CpG or ODN-CTR injections (B). Graphs show the growth of distant parental tumors. Results shown are representative of two separate experiments. (A) P < 0.05 between CCL20 and mock groups; (B) P < 0.05 between CCL20 + CpG and the other groups. (C and D) Mice were inoculated with 2 × 106 CT26 parental tumors, and 0.1 μg of recombinant CCL20 protein or PBS was injected daily for 3 weeks into the tumors beginning 1 day after tumor inoculation. Results shown are from three separate experiments. *Statistical difference in tumor growth between mice treated with CCL20 compared with untreated mice (P < 0.05). (E and F) Mice were inoculated with 5 × 104 B16 parental tumors, and recombinant CCL20 protein was injected into the tumors alone or in addition to five intratumoral injections of CpG as described in Methods.