Grants and Contracts Details
Cigarette smoking induces lung and upper airway squamous cells carcinomas (SCC) that have a grim prognosis, especially after metastasis. Our long term goal is to design SCC treatments that stimulate immune attack. SCC are recognized by natural killer receptors, including NKG2D. Although human NKG2D ligands, including MICB abd ULBP1, can engage NKG2D and activate natural killer cells, NKG2D ligands may play complicated roles in immune regulation. We can show that metastatic SCC resist human natural killer attack, but paradoxically upregulate MICB. Airway SCC selectively suppress ULBP1 expression, but suppression is reversed by proteasome inhibitor drugs. We hypothesize that MICB facilitates SCC metastasis, whereas ULBP1 inhibits SCC growth in vivo. We also propose that SCC differentially suppress ULBP1 expression and that drug-indiced ULBP1 regulation cannot be explained by current paradigms. To test these hypotheses, we will measure MICB, ULBP1, and other NKG2D ligand RNA in airway promary SCC tumors and lymph node metastatic tumors from the same patient, test whether enforced MICB or ULBP1 expression changes SCC growth and metastasis in T cell-deficient mice. We will identify the signaling mechanisms and cis-acting genetic elements that differentially control ULBP1 expression in response to proteasome inhibitor drugs. In our translational research, results with human biopsy specimens will lead to new hypotheses that will be tested in cell lines and in experimental animals. Our results will be highly significant, because they will help us understand how SCC escape immune destruction and metastasize to distant sites. Our research may lead to new therapies that make airway SCC more susceptib;e to immune attack.
|Effective start/end date||9/1/07 → 2/28/10|
- KY Lung Cancer Research Fund: $144,086.00
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.