A Combined Nutritional and Immunological Intervention to Activate Natural Cytotoxicity against Breast Cancer Cells in Vitro and in Vivo

  • Ross, A. Catharine (PI)

Project: Research project

Project Details

Description

PUBLIC ABSTRACT

Many nutrients, including vitamin A, have been proposed to have anti-cancer activity. The natural active metabolite of vitamin A, retinoic acid (RA), is well known for its ability to inhibit the growth of breast cancer cells and other types of tumor cells, and to help immature cells become normal mature cells. Immune stimulation also can be important in helping the body detect and fight abnormal cells and tumor cells. The idea in this proposal is that a nutritional-immunological combination will act together to significantly increase the body¿s natural ability to kill breast tumor cells. Natural immunity is due to several types of cells, including dendritic cells that sense "danger" and can respond by producing proteins known as cytokines; Natural Killer (NK) cells that can spontaneously recognize and kill tumor target cells; and a special type of T-cell, referred to an invariant NK-T cell (iNKT cell), that has been shown in the last few years to have great potential against various cancers. Each of these cell types, dendritic cells, iNKT and NK cells, can be stimulated to a higher level of function. When activated, the cells produce more or different cytokines resulting in increased killing of kill tumor cells.

Recently, we have discovered that RA causes a large increase in a specific molecule called CD1d that is present on human and animal monocytic cells. CD1d is essential for the activation of iNKT cells. We are now proposing that by using RA to increase CD1d, it should be possible to achieve greater activation of iNKT cells when these cells are further exposed to a molecule known as alpha-GalCer. Alpha-GalCer alone has already shown anti-cancer potential. We now believe that RA will initiate a train of events, beginning with elevated CD1d, that will allow binding of more alpha-GalCer and result in increased activation of iNKT cells. This should increase the release of cytokines that, in turn, will stimulate NK cells to be more effective tumor killers. We are also planning to test another agent, poly-I:C, for its ability to activate dendritic cells to release more of the types and amounts of cytokines favorable for NK cell activation. NK cells are an attractive target for cancer therapy because NK cells are mobile and they can migrate to tumor sites, spontaneously attack tumor cells, and recycle to kill more than one tumor cell. NK cells are an important component of the body's natural surveillance system, and it should be possible to increase their function by providing the right combination of stimulating agents. To our knowledge, the primary agents we are planning to test -- RA, alpha-GalCer -- have never been tested together, nor all three combined.

Regarding applicability, we envision that promising results from the therapy we will test in mice, using RA and alpha-GalCer, with possible addition of Poly-I:C, could be translated into human clinical studies without significant delay. Each of the agents of this new triple combination is relatively inexpensive and each has undergone significant testing. Indeed, RA is already used to treat leukemia. The technology for in vitro cell activation and transfer has been established. Also, if the results of our animal studies are promising, the treatment could be tested further with other cancer models. Alpha-GalCer has been shown to be effective in mice against melanoma and lung cancer, so if RA treatment combined with alpha-GalCer is effective in reducing breast tumor growth in our studies, additional studies in other models of cancer would be warranted. We believe the triple combination we are suggesting would not preclude other traditional cancer therapies, such as radiation, but this would require additional testing in animal studies.

Benefits for the cancer patient would include a procedure that is relative simple, with very low exposure to drugs (patient cells obtained from blood could be treated and then re-infused a day or so later). Regarding risk, while alpha-GalCer has shown remarkable anti-tumor effects, liver iNKT cells were overactivated when injected alpha-GalCer was injected i.v, in mice with liver disorders. An advantage to our approach is that RA and alpha-GalCer will be added to cells in culture, and it might not be necessary to administer them in vivo. If we find this is so, then whole-body exposure to these agents could be kept very low. The intervention we are proposing should not preclude the use of other traditional cancer therapies, such as radiation, while it could provide an additional new means to fight breast cancer or other tumors.

Our studies will advance the understanding of nutritional-immunological treatments for cancer. They will help to define a specific mechanism by which RA, combined with other simple and available agents, can stimulate the body¿s immune system to fight breast cancer more effectively. Our new findings, especially regarding the effect of RA on CD1d, will stimulate other researchers studying iNKT cells to consider how RA and other nutrients can be used to boost natural immunity.

StatusFinished
Effective start/end date1/1/0612/31/06

Funding

  • U.S. Department of Defense: $434,038.00

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