Our traditional way of thinking about the immune system focuses on protection against viruses and bacteria. However, as research on the immune system continues, we are now finding that the contributions of the immune system to both health and disease are very complex. The immune system can be thought of as a highly diffuse organ that is integrated in some way or another with every other organ (skin, kidney, etc.) in the body. The immune system not only serves as a barrier against disease, but it is also has a routine role in the day-to-day function of various organs. The immune system maintains the health of the individual in many different ways. However, it is now understood that the immune system can also be involved in disease processes and pathogenesis. In breast cancer, T cells populate tumor tissue very early in the course of disease (e.g., T cells are detected in benign proliferative disease) and are among the most abundant immune effectors in early and advanced tumors. The typical idea, as modeled in other cancers, suggests that T cells are beneficial to survival and protect against malignancy. Indeed, this is the basis and rationale for the development of cancer vaccines. For example, in ovarian cancer, the more T cells in the tumor, the better the prognosis for the patient. Such findings have never been found in breast cancer, however. Rather, the presence of T cells in breast cancer tissues is associated with a worse outcome. This was first reported in the science literature in 1989 by investigators who found that as the numbers of CD8 T cells (i.e., cytotoxic T cells) in the tumor increase, the number of axillary lymph nodes with metastatic disease also increase. In contrast to other cancers, there has never been a clear association between T cells and improved survival or reduced tumor size in breast cancer. It is likely that any protective impact of the T cells is overshadowed by some kind of negative impact. It is not yet known what this negative effect is, but a recent publication suggests that T cells can increase the aggressiveness of the tumor cells by a long-known biologic process referred to as epithelial to mesenchymal transition (EMT). EMT is a natural biologic process by which cells acquire the ability to move from one area to another. For example, during development of a fetus, cells must move to form new organs, arms, legs, etc. Cells use EMT to move. Breast cancer cells also use EMT to move (i.e., invasion and metastases). We think that T cells and other cells of the immune system can cause breast tumor cells to undergo EMT.
Our hypothesis in these studies is that immune cells cause breast cancer cells to undergo EMT. Furthermore, we also hypothesize that the tumor cells that have undergone EMT are immunosuppressive and may limit any antitumor activity of the immune system. In support of this hypothesis, it has been shown, in murine models, that tumor-specific T-cell-mediated immune responses can cause epithelial breast cancer cells to undergo EMT, increase immunosuppressive capabilities, and downmodulate expression of signals that alert the immune response.
The objective of the proposed study is to define the interactions between T cells and breast cancer. We have two specific aims. In Specific Aim 1, we will determine if T cells and other cells of the immune system can directly cause breast tumor cells to undergo EMT. In vitro studies will be done to determine the mechanism by which T cells mediate EMT. We will also use a mouse model of breast cancer to identify the important immune effects, besides T cells, that may be involved in this process. In Specific Aim 2, we will ask if breast tumors cells that have undergone EMT have increased capabilities of immunosuppression compared to native epithelial breast cancer cells. Our goal in this aim is to determine if breast cancer cells that have undergone EMT produce immunosuppressive substances. The immune system interacts with breast cancer from the time of its inception through its most advanced stages.
Increasing evidence now supports the notion that the immune system, aside from its antitumor role, can also drive malignant progression and immune escape of breast cancer. In this proposal, the innovative goal is to define a newly identified pathologic interaction between the T lymphocytes and breast cancer. With very limited successes, much effort has been put toward developing immune-based therapies (e.g., vaccines) for the treatment and prevention of breast cancer. Further unlocking the natural interactions between the immune system and breast cancer will be required to improve our immunotherapeutic capabilities.
|Effective start/end date||1/1/06 → 12/31/06|
- U.S. Department of Defense: $111,000.00