Researchers find how to generate an immune response in mice
A research team with members from Japan and the US has discovered a means of inducing persistent immunity to tumors in mice. In the long term, the work could lead to a vaccine against certain tumors in people.
Unlike infectious organisms and foreign tissue, tumor cells do not elicit a powerful immune response naturally. In particular, tumors do not activate the production of immune CD4+ and CD8+ T-cells geared to fighting them. This typically needs two signals. In addition to a compound known as an antigen which is specific to the tumor and reacts with a T-cell receptor when presented by dendritic cells (DCs), it also requires a co-stimulatory molecule that tumors appear to lack.
In a recent paper in the Journal of Experimental Medicine1, the research team—comprising members from RIKEN’s Research Center for Allergy and Immunology in Yokohama and The Rockefeller University in New York—detailed a method for inducing immunity in mice to four common tumors lasting up to 12 months.
A glycolipid compound derived from marine sponges known as α-galactosylceramide (α-GalCer) can activate the immune system’s natural killer (NK) and natural killer T-(NKT) cells against tumors, but alone does not protect mice from cancers such as B16 melanoma. The researchers found, however, that a low dose of B16 tumor cells loaded with α-GalCer and injected intravenously will induce a protective immune response to B16 melanoma. The same was true for three other mouse tumors which normally generated a poor immune response.
To trace what was taking place, the team tracked labeled α-GalCer-loaded tumor cells under the confocal microscope. They found that α-GalCer did indeed activate NK and NKT cells to kill tumor cells (Fig. 1a, b). Debris from the dead cells was captured by DCs in the spleen. These DCs then changed or matured to mount an immune response by presenting tumor antigen peptide in such a way as to stimulate the production CD4+ and CD8+ T-cells against that particular tumor (cross-presentation 1) (Fig. 1c). In addition, the mature DCs presented the original α-GalCer to NKT cells again, stimulating further response (cross-presentation 2) (Fig. 1d). Immunity against individual tumors persisted for at least six months.
“We now have a mouse model for generating an immune response to tumors,” says project coordinator Shin-ichiro Fujii. “We can use it to focus on questions of basic science, such as what triggers the immunity. We would also like to extend the research into human patients.”
Shimizu, K., Kurosawa, Y., Taniguchi, M., Steinman, R.M. & Fujii, S. Cross-presentation of glycolipid from tumor cells loaded with α-galactosylceramide leads to potent and long-lived T cell-mediated immunity via dendritic cells. Journal of Experimental Medicine 204, 2641–2653 (2007).