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Rodents as Models for Biomedical Research

Vaccine cures lung cancer in mice

May 18, 2000: In this month's issue of Nature Biotechnology (1), a research group led by Dr. Wilfrid Jefferies at the University of British Columbia's Biomedical Research Centre report on a method for enhancing the ability of the immune system of mice to recognize and attack cancer cells. The technology, which has potential as a cancer therapy in humans, has been licensed to GeneMax Pharmaceuticals Inc., based in Vancouver, British Columbia.

Cytotoxic T lymphocytes (Tc cells) are at the core of the mammalian cell-mediated immune response. Their role is to identify and kill cells infected by a virus or other intracellular pathogen, thus limiting the spread of infection. They can also recognize and attack cancer cells, and it is this type of cell-mediated immunity that constitutes the body's primary defense against cancer.

The Tc cells identify cells for attack by recognition of small peptides or antigens bound to molecules at the cell surface known as class I major histocompatibility complexes (MHCs). The antigens, which may be derived from viral or bacterial proteins or proteins unique to cancerous cells, become bound to class I MHCs within the lumen of the endoplasmic reticulum (ER), where they are conveyed by transporters associated with antigen processing (TAP proteins). The class I MHCs, with their associated antigens, are then conveyed to the cell surface, where depending on the origin of the associated antigens, they may trigger Tc cell attack.

However, cancer cells have developed a multitude of strategies that allow them to hide from the immune system. Dr. Jefferies' team hypothesized that reduced synthesis of TAP proteins might be one such strategy. The lack of transport of antigens into the lumen of the ER would prevent association of tumor antigens with class I MHCs, with the result that tumor-associated antigens would not be conveyed to the cell surface where they would trigger Tc cell attack. Restoration of proper antigen processing within these TAP-deficient cells by the introduction of one or more genes encoding the missing transport proteins could eliminate the subversive behavior of these tumors.

One way the TAP genes could be introduced into the cancerous cells would be to insert them into the genome of a virus with which the tumor cells could be infected. The vaccinia virus, used in the past for vaccination against smallpox, can be genetically engineered to express a variety of proteins including mammalian TAP proteins. Thus, if TAP-deficient tumor cells are vaccinated with recombinant vaccinia virus expressing the TAP gene, and the TAP proteins produced by the virus are effective in transporting tumor antigens into the lumen of the endoplasmic reticulum, then class I MHCs bearing tumor antigens should appear at the cell surface and elicit Tc cell attack.

The UBC researchers tested this hypothesis in mice infected with small-cell lung carcinoma CMT.64, a member of the TAP-deficient class of tumors. They then vaccinated the mice with a genetically engineered vaccinia virus containing the TAP1 gene, which encodes a subunit of a transporter associated with antigen processing. What they found was that the mean survival time of the vaccinated mice was twice that of control mice. Moreover, by the end of the experiment, a significant number of the vaccinated mice were tumor-free.

These results support the hypothesis that TAP protein deficiency in some tumors contributes to their ability to hide from the immune system, and that delivery of TAP1 to cancer cells in vivo can restore antigen processing in these cells. The technology may have the advantage of being widely applicable to a variety of human cancers, because it does not target any one particular type of antigen; rather, it compels each type of tumor to express its own unique surface markers, thus reestablishing the immune system's innate ability to recognize and destroy these aggressive cells.


REFERENCES

(1) Alimonti, J., Q.-J. Zhang, R. Gabathuler, G. Reid, S.S. Chen and W.A. Jefferies. 2000. TAP expression provides a general method for improving recognition of malignant cells in vivo. Nat. Biotechnol. 18:515-520.



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