Cytokine targeting of dendritic cells to tumors produces dramatic anti-cancer activity

Dendritic cells are believed to play a critical role in antitumor immune responses. These cells are the most potent antigen presenting cells known, uniquely capable of inducing immunity to newly introduced antigens. Normally, dendritic cells reside as immature cells in peripheral tissues however under certain conditions they take up and process antigens and also undergo activation and maturation. Mature cells prime specific CD4 and CD8 T cells to these antigens. Tumors however are characterized by the presence of immature dendritic cells that are unable to stimulate T cells. Defects in dendritic cell maturation and activation may prevent effective antitumor responses and may even induce immune tolerance.

Activation and maturation of dendritic cells ex vivo and their subsequent reinfusion to tumor-bearing recipients after a pulse with tumor antigen offers one approach to bypassing defects in the immune recognition and the destruction of tumors. This process is however time consuming and costly.

In the March edition of the Journal of Clinical Investigation Furumoto et al report a recently developed approach which avoids the dependence on ex vivo dendritic cell activation and reinfussion of these cells. Instead this Stanford University group have shown that increasing tumoral levels of the chemotactic chemokine, CCL20/macrophage inflammatory protein-3alpha (MIP-3alpha) stimulated the movement of endogenous dendritic cells into the tumor core. Increased tumoral levels were produced by forcing the tumor cells to express the chemokine. Stimulating the infiltration of dendritic cells in this fashion led to complete regression of colon tumors. Stimulating the infiltration of dendritic cells also produced therapeutic immunity against melanomas although in this case intratumoral injection of CpG to induce dendritic cell maturation was required for therapeutic activity. In this instance the effect of CpG was to restore the capacity of CCL20-mobilized dendritic cells to cross-present tumor antigens through the MHC-1 pathway, prime antigen-specific naive CD8 T cells and stimulate antigen-specific effector CD8 T cells.

The Stanford University group also investigated the differences between the dependency of dendritic cells on CpG for anti-tumor efficacy against colon cancer and melanomas. They found that the latter but not the colon cancer tumors secreted factors able to down-regulate CD86 co-stimulatory molecules on dendritic cells and inhibited their ability to activate allogenic T cells. This effect was reversed by CpG.

These data demonstrate that the delivery of CCL20 protein alone or in combination with CpG offers new possibilities for the treatment of patients with accessible tumors. Although these findings offer considerable hope for the treatment of cancer a number of issues are outstanding.

Firstly tumor metastasis presents a fundamental clinical problem. Of the 160,000 patients seen yearly in the United States with colon cancer, as many as 40-50% develop metastatic liver cancer and once this occurs cure is rare. Likewise, metastasis converts melanoma from a highly treatable condition to one with little hope. Whether increased CCL20 levels in the primary tumor can have an effect on distant tumors is therefore an important issue. In the present study, Furomoto show that the induction of CCL20 expression in primary tumors can indeed reduce the size of distant tumors. Although the regression of the distant tumors was incomplete, 50% reductions were observed.

Secondly the dependence on inducing tumor cells to express CCL20 in order to obtain efficacy introduces potential limitation. Instead it would be considerably more convenient to employ endogenous CCL20. Injecting CCL20 directly into the tumor was found to be only moderately successful in animals with colon tumors and melanomas. This suggests that in order to harness the therapeutic potential of CCL20, strategies will depend on the development of gene therapies or other strategies able to induce CCL20 expression within tumors or on improved delivery of therapeutic proteins. Both areas of medicine are advancing and it is therefore hoped that such advances will allow the full therapeutic benefits of CCL20 therapeutics to be reaped. In addition, further research into identifying factors released by melanomas to down-regulate CD86 co-stimulatory molecules on dendritic cells may lead to the development of small molecule therapeutics that bypass the dependence on intra-tumoral CpG administration.

Entry date Tuesday, June 08, 2004

Adapted from Furumoto et al, J Clin Invest. 2004 Mar;113(5):774-83.