Understanding optimized immune therapy

22 September 2006 (Volume 1 Issue 11)

A single agent efficiently activates multiple arms of the immune response

Figure 1: α-C-GalCer inhibits tumor metastasis in mice. When co-injected with tumor cells, DCs pulsed with low doses of α-C-GalCer (CG/DC) effectively suppress the spread of tumor cells (blue spots) to the lungs. Higher doses of α-GalCer (G/DC) are required to achieve the same effect.

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PNAS/National Academy of Sciences/103/11255 (2006)

In clinical trials worldwide, therapies capable of harnessing the power of the immune system show promise in treating infections and malignancies.

At the RIKEN Research Center for Allergy and Immunology in Yokohama, Shin-ichiro Fujii and colleagues have identified molecular mechanisms underlying the potent immunostimulatory capability of one such therapy. Their focus was on the glycolipid α-galactosylceramide (α-GalCer), which triggers strong protective immune responses.

Within the body, ‘foreign’ substances such as microbes or abnormal tumor cells are captured by and displayed on the surface of dendritic cells (DCs). Passing immune cells called natural killer T (NKT) cells are equipped with sensors that allow them to recognize bits of foreign substances decorating the surfaces of DCs. NKT cells that detect foreign substances relay warning signals, in the form of cytokines and co-stimulatory molecules. These signals alert other immune cells to the presence of ‘non-self’.

It has been established that when α-GalCer is presented by DCs, it activates NKT cells, and exhibits therapeutic activity in mouse models of cancer and infectious disease. However, a slightly modified version of α-GalCer, called α-C-GalCer, exhibits 100 and 1,000-fold greater potency in fighting tumor metastases and malaria infections, respectively.

Fujii and colleagues examined the consequences of intravenous injections of graded amounts of α-GalCer or α-C-GalCer into mice (Fig. 1). As reported in the Proceedings of the National Academy of Sciences¹, they found that substantially lower doses of α-C-GalCer were needed to effect release of cytokines from DCs and NKT cells. Further, α-C-GalCer selectively amplified production of cytokines that are particularly adept at killing transformed and infected cells.

Although both glycolipids were equally capable of promoting the appearance of co-stimulatory molecules on the surface of DCs, less α-C-GalCer was needed to trigger expression of co-stimulatory molecules on NKT cells.

When co-injected with tumor cells, low amounts of α-C-GalCer were sufficient to elicit immune protection against subsequent challenges with tumor cells.

Less time was required to ‘load’ α-C-GalCer onto DCs, and DCs loaded with α-C-GalCer retained their ability to stimulate NKT cells for a prolonged period of time. “These observations suggest that more efficient and stable presentation underlie the enhanced potency of α-C-GalCer, although factors other than stability might also contribute,” says Fujii.

The team’s work highlights facets of the immune response that correlate with clinical efficacy, which may be important parameters to consider during future experiments aimed at designing optimal immune therapies.

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1. Fujii, S., Shimizu, K., Hemmi, H., Fukui, M., Bonito, A.J., Chen, G., Franck, R.W., Tsuji, M. & Steinman, R. Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice. Proceedings of the National Academy of Sciences USA 103, 11252–11257 (2006). |article|