Restoration of Immune Surveillance in Lung Cancer by Natural Killer Cells
Abstract
This application probes the mechanism by which tobacco products such as nicotine suppresses the immunity system, namely natural killer (NK) cells. NK cells are potent immune cells because they circulate in the blood and organs to seek and destroy newly forming tumor cells. This is done through multiple receptors on NK cells that can recognize unique proteins that appear only on nascent tumor cells. These receptors are anchored on the NK cell surface by another protein called DAP12. We recently discovered that tumor cells have the ability to escape NK cell recognition because they can produce a protein called transforming growth factor-beta that disrupts expression of DAP12 so that the tumor-cell seeking receptors cannot be displayed. We found that this immune suppression is done by a microRNA, miR183, in NK cells, which specifically binds to DAP12 gene to destroy it. Therefore, NK cells exposed to tumor cells will no longer have DAP12 to anchor the tumor-recognizing receptors, inactivating them. We now find that nicotine from tobacco smoke can also activate the same mechanism in NK cells. Without immunity, cancer cells can grow unchecked. The experiments proposed here will shed light on the role of miR183 as a novel, specific regulator of NK cell function against lung cancer and whether we can target miR183 to recover NK immunity to treat early stage lung cancer. Most immunotherapeutic strategies are first tested in mice for proof of concept, and we have designed an innovative strategy that uses immunodeficient NSG mice that can accept human tumors and human NK cells. We have already demonstrated that NSG mice bearing human lung tumors can be cured if human NK cells are administered at the same time as the tumor. However, if we delay NK cell administration by 7 days after the tumor is established in the mice, these NK cells are no longer effective, likely due to the tumor cells producing immune suppressive factors. Using this model, we intend to use anti-sense miR to restore NK cell function and improve survival and tumor regression. This strategy has never been tried in man and constitutes a new approach to treat early-stage lung cancer. There are numerous advantages for immunotherapy of lung cancer. Tobacco smoke contains carcinogenic compounds such as nicotine that can cause mutation in any one of multiple tumor suppressors or oncogenes to drive cancer development, giving rise to heterogeneic phenotypes. Lung cancer patients are therefore distinctly disadvantaged, given their poor response to chemotherapy due to this tumor heterogeneity. Tumor immunity, on the other hand, has the unique ability to target any tumor type in a cancer patient and remains specific, capable of seeking out aberrant tumor cells to prevent recurrence and metastasis. Our innovative anti-sense miR183-based strategy could provide long-term immune memory against lung cancer, as it is widely established that NK cells can interact with other immune cells, called antigen-presenting cells and T cells, to generate long-lasting adaptive immunity, which can translate into complete cure. More importantly, the stable anti-sense miR183 nanoparticles can serve as "off-the-shelf" reagents immediately applicable to treat cancer patients. Nanoparticles have been proven to be safe and biodegradable in past clinical trials. The Moffitt Cancer Center is uniquely positioned to conduct these trials, given that we treat about 800 new lung cancer patients per year. Most importantly, the Immunology Program is one of the premier translational programs in the United States, with several physician scientists, including Drs. Jeff Weber and Scott Antonia, conducting vaccine and adoptive T cell therapy of cancer. The Phase I Clinical Trial Unit and the Cell Therapies Resource Facility will facilitate these clinical trials, if miR-based immunotherapy is proven to be efficacious in our humanized mouse models. Future studies could include combination ther
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510400
Entities
People
- Julie Djeu
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army