Innate Immune Response to Head and Neck Cancer Stem Cells
Initial Award Abstract
Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignancy of the mucosa lining structures that include the oral cavity, paranasal sinuses, pharynx, and larynx. It is the most common neoplasm of the upper aerodigestive tract. Over 500,000 new cases, representing approximately 6% of all cancer cases worldwide, are estimated to be diagnosed annually. While there have been some modest improvements in the treatment of advanced cases, recurrence rates are still as high as 30-50%, and the therapy alone – which includes a combination of surgery, chemotherapy, and radiation – often results in significant morbidity and long-term functional toxicity, negatively affecting critical functions such as speech and swallowing.
Epidemiological evidence strongly indicates an association between the incidence of this malignancy and exposure to tobacco carcinogens that come into contact with the upper aerodigestive tract mucosa through either inhaled smoke or directly from chewing tobacco. These carcinogens can induce mutations in cells, eventually resulting in uncontrolled proliferation of cells and cancer formation.
Very recently, a new understanding of how solid tumors develop was revealed. It was shown that tumors arise from a rare subset of cells within a tumor and that these cells have properties akin to those of normal healthy adult stem cells. For this reason, these tumorigenic cells have been called cancer stem cells. The importance of this finding lies in the observation that cancer stem cells appear to be more resistant to conventional chemotherapy and radiation therapy. Thus, novel therapy will need to be directed toward the eradication of these cells.
Approximately a century ago, the Nobel laureate Paul Erhlich initially proposed the idea that the immune system can recognize and respond to cells undergoing malignant transformation, but this idea has only recently been able to be vigorously explored given the advances in molecular immunology. Over the past decade, the innate immune system has been shown to be exceptionally well designed for the surveillance of cells undergoing transformation. The immune cell population that is particularly effective in this frontline response is a special subset of white blood cells (or lymphocytes) called natural killer (NK) cells.
For reasons that are still not clear, the innate immune system in certain individuals who appear to be otherwise normal can fail to respond and control malignant transformation. To understand why this is the case, it will be important to explore the interaction between cancer stem cells and the innate immune system, particularly the NK cell subset of lymphocytes. A current limitation hindering our ability to explore this interaction is the lack of an animal model of head and neck cancer stem cells. Because the best-characterized animal model for studying the immune system is the mouse model, we propose to develop a mouse model of head and neck cancer stem cells. In this model, we will induce oral cavity cancer with a carcinogen found in tobacco. The tumors will be labeled with a marker that will allow us to separate the cancer stem cells from the rest of the tumor cells. Then, we will be able to address questions regarding how the immune system in these mice can recognize and control these malignant cells. The information obtained will contribute greatly to our goal of developing effective immunotherapy to treat head and neck cancer. |