Areas of Interest - Basic Research

Dendritic Cells

Dubinett: see lung cancer
Kiertscher: The long-term goal of our work is to understand the regulation of immune responses to cancer and to use this information to develop an effective form of cancer immunotherapy. To achieve this goal we must first study the cellular events involved in the initiation of the immune response to cancer and determine the most effective means to manipulate these events to generate anti-tumor immunity. Dendritic cells (DC) are potent antigen-presenting cells, and are an integral part of the immune systems' response to cancer. Research by ourselves and by others has found that these cells are defective in cancer patients. However, cells removed from the patients and cultured with cytokines in the lab are capable of regaining their functional activity.

In a study currently underway, DC have been successfully generated from the blood of breast cancer patients. These cells display the high levels of expression of cell surface molecules characteristic of DC, and are being evaluated for their ability to generate tumor-specific responses in vitro, in preparation for future use in therapy. We hypothesize that the processing and presentation of multiple tumor antigen epitopes by DC is the most efficient and effective way of stimulating T cell responses. In this study, we are comparing various methods of arming DC with tumor antigens, including 1) purified immunodominant peptides which are specific for asingle antigen and a single Class I MHC molecule, 2) transduced cDNA encoding for a single tumor antigen which will allow the recipient DC to intrinsically process and present all possible antigenic peptides (immunodominant and sub-dominant) within the context of all available MHC molecules, and 3) extracts from autologous whole tumor cells which will provide a broad mix of tumor antigens (both defined and undefined antigens)for processing and presentation. The information obtained from this study will further our understanding of the interactions between DC and T cells which lead to the generation of anti-tumor immune responses. This understanding will be valuable in the development of immunotherapeutic treatments for cancer.

In a second project, we are examining ways by which tumors evade the immune response, resulting in the growth and progression of lung cancer. Tumors produce immunosuppressive factors, which may aid in their ability to prevent an effective immune response. We hypothesize that the immunosuppressive effect of lung tumor-derived factors on DC may be one mechanism by which tumors evade detection and killing by immune cells. Our studies have shown that factors produced by lung tumor cells induce defective maturation and programmed cell death (apoptosis) in developing DC. By inducing apoptosis of DC, lung tumors effectively reduce the possibility that the DC will interact with and stimulate tumor-specific T cells. Currently, we are determining the molecular pathways, which are involved in the defective maturation and apoptosis of DC. These results will add to our understanding of the regulation of DC development, and the means by which this regulation is disrupted by tumors. Since DC are a critical component in the initiation and maintenance of the immune response to tumors, understanding the effects of these factors on DC will have important implications for the design of new treatments.

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