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 + CpG but not Flt3L + CpG induces a therapeutic antitumor response...
CCL20 + CpG but not Flt3L + CpG induces a therapeutic antitumor response against B16 melanoma. (A and B) Graphs show tumor growth and survival of mice inoculated with 5 × 104 CCL20-transduced B16 tumor cells (CCL20) or mock-transduced tumor cells alone or in addition to two or five intratumoral injections of CpG or ODN-CTR. Arrows show the days of CpG injections. (C and D) Mice were inoculated with B16-CCL20–transduced tumor cells followed by two or five intratumoral injections of CpG or with B16-mock–transduced tumor cells followed by two or five intratumoral CpG injections alone or in addition to eight daily injections of Flt3L beginning on the day of tumor inoculation (mock + CpG + Flt3L). Results shown are representative of six different experiments in A and B and two different experiments in C and D. (A) P < 0.05 between CCL20 + CpG and control groups. (B) Survival rate was higher in mice treated with CCL20 + 5 CpG compared with mock + 5 CpG (P < 0.0001) or to CCL20 + 5 ODN-CTR (P = 0.0006). (C) P < 0.05 between CCL20 + CpG and the other groups. (D) Survival rate was significantly higher in mice treated with CCL20 + CpG compared with mock + CpG + Flt3L (P = 0.0012). *P < 0.05.