Lung squamous cell carcinoma (LSCC) is the second most common type of lung cancer. LSCC has a very dismal five year survival rate of 15% and causes approximately 400,000 deaths worldwide every year. Although common genetic alterations in LSCC have been characterized, numerous targeted therapies have been ineffective in the treatment of this deadly disease. Hence, LSCC clinical care had been limited to chemotherapy and radiotherapy until recently when the first immune checkpoint inhibitor was FDA-approved in 2015. Immune checkpoint inhibitors block intercellular ligand ? receptor signaling to reactivate cytotoxic T-cells to target cancer cells. Immune checkpoint blockade can lead to durable responses (i.e. complete and long-lasting tumor regression) even for advanced metastatic cancers, but the effectiveness of these therapies for LSCC is limited with 15-33% objective response rates. In addition, tumors that initially respond eventually acquire resistance to immunotherapies. Therefore, it is of the utmost importance to understand which factors promote tumor immunity and which factors drive immune evasion in order to improve cancer immunotherapy. Since many immune cell types are present within or surrounding tumors, it is challenging to understand the contributions of each immune cell type and the cancer cells in tumor immunity. Recent studies showed that tumor-associated neutrophils (TANs) correlate with adverse prognosis in many cancer types, including lung cancers, and can promote both primary tumor growth and metastasis. In light of the clinical significance and recent literature, the goal of this project is to identify the genetic determinants of TAN activation and the function of TANs (i.e. pro-tumorigenic, neutral, or anti-tumorigenic) in LSCC. Recent studies suggest that tumor histopathology may be the driver of TAN activation, but the exact mechanism is yet to be elucidated. My preliminary data suggest that the oncogenic transcription factors SOX2 and NKX2-1 both impact TAN activation in opposite manners in lung cancer independent of histopathology. Based on my preliminary data, I hypothesize that SOX2 activates pro-tumorigenic TANs through NKX2-1 suppression in LSCC. To test this hypothesis, I will use our novel immunocompetent genetically engineered mouse models of LSCC to: 1) Determine whether NKX2-1 suppression is necessary for SOX2-driven neutrophil recruitment to tumors; and 2) Determine whether TANs are pro-tumorigenic and inhibit activity of T cells in tumors. Identifying the role of TANs and the underlying genetic mechanisms that control their activity is important because these data will determine whether targeting TANs can be a novel immunotherapy strategy for LSCC treatment. Inhibition of TANs or reversal of their phenotype to become anti-tumorigenic may provide a novel immunotherapy strategy that could be combined with existing treatments to improve patient survival.
Immunotherapies were recently approved for lung squamous cell carcinoma, which is one of the most common and deadly cancer types, but it is currently unclear why only subsets of patients respond. This study aims to uncover how the oncogenes that drive this devastating disease regulate neutrophil recruitment to tumors and what role neutrophils play in tumor immunity. A better understanding of how cancer cells hijack neutrophils to promote tumor growth will identify novel immunotherapy targets and hence improve the quality of life and survival of lung cancer patients.
| Mollaoglu, Gurkan; Jones, Alex; Wait, Sarah J et al. (2018) The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity 49:764-779.e9 |
