Lung Squamous Cell Carcinoma Stem Cells as Immunotherapy Targets
Abstract
This proposal addresses at least two of the Lung Cancer Research Program Area of Emphasis: Understanding predictive and prognostic markers to identify responders and non-responders and understanding susceptibility or resistance to treatment. Squamous cell carcinoma (SCC) of the lung is a devastating disease that has a very high mortality rate. Thousands of military personnel and their families will be affected by lung SCC this year alone. The standard of care for late-stage lung SCC is the chemotherapy docetaxol, which can prolong survival to a median 5-year survival rate of less than 5%. However, a new clinical trial recently demonstrated that in some lung SCC patients, survival could be increased by administration of the immunotherapy Nivolumab. These results are exciting and have catapulted immunotherapy to the forefront of treatment regiments considered for lung SCC patients. Nivolumab has now been approved as a second-line therapy for lung SCC. Importantly, it is still not understood why immunotherapy works very well in some patients but not others. In addition, there is no way to predict response to immunotherapy in each patient. It is already clear in some patients that their tumors are becoming resistant to even this new form of therapy. In order to maximize the benefit of immunotherapy for all lung SCC patients and to know proactively how to combat resistant disease, understanding the mechanisms within the tumor and the microenvironment that ultimately determine how and when a patient will benefit from this new class of treatment is needed. The proposed studies will address this gap in lung cancer by testing the idea that a special subset of lung cancer cells, called cancer stem cells (CSCs), are the targets of immunotherapy and can be used to monitor treatment response and resistance. CSCs within many different types of cancer have been shown to contribute to treatment resistance. However, CSCs from lung SCC have not yet been discovered. Identification and understanding of CSCs offer a new way to understand SCC. We recently developed the first mouse model of lung SCC that mimics lung SCC that develops in patients. This new mouse model allows for multiple new avenues of research to elucidate methods to detect early-stage tumors, treatment possibilities, and how drug resistance occurs. We discovered biomarkers to detect the CSCs in this mouse model of SCC. Importantly, the CSCs in these mouse tumors had high levels of the molecules targeted by immunotherapy. This finding prompts the exciting hypothesis that CSCs are able to drive disease progression and drug resistance because they can avoid the immune system. The proposed studies will discover CSCs in human lung SCC and determine if immunotherapy changes CSC numbers or activities in lung SCCs. Our mouse model has also already shown that lung SCC can become resistant to immunotherapy. We can now use these mice to learn how to combat immunotherapy-resistant lung SCC in real time while patients are already undergoing this new therapy. For example, we will test drugs to use in combination with immunotherapy to eliminate resistant tumors. Our findings will provide new ways to think about targeting squamous lung cancer, and specifically will inform the optimal use of immunotherapy for this devastating disease. The ultimate outcome of this research will be extending the survival of lung cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610260
Entities
People
- Carla F Kim
Organizations
- United States Army