Lung cancer is the leading cause of cancer deaths worldwide, accounting for ~160,000 lives each year in the US alone. Making matters worse, five-year survival rates remains a dismal ~15%, highlighting the need for new and effective therapies. One approach to treat lung cancers is to optimize the function of the host immune system to fight tumors. In many cases, cancer cells are able to manipulate host immune cell function to the benefit of the tumor. The key proteins that regulate the signaling pathways cancer cells use to skew immune cell function remain poorly defined. In order to restore immune function in cancer, we must first identify the exact mechanisms that cancer cells use to recruit and manipulate immune cells. We have identified the signaling adaptor protein, insulin receptor substrate-1 (IRS-1) as a key entity that limits the ability of cancer cells to manipulate host immune responses. IRS-1 functions to homeostatically regulate the IL-22 signaling pathway in cancer cells. In its absence, enhanced JAK/STAT activity results, causing increased production of immune cell recruiting molecules (cytokines), which promotes tumor-associated inflammation. Using a variety of mechanisms, this tumor-associated inflammation promotes lung tumor growth and invasiveness. The purpose of this study will be to determine exactly how IRS-1 suppresses the ability of cancer cells to produce cytokines, and to identify key steps in these pathways that would represent novel therapeutic targets.
Most lung cancers are able to manipulate the host immune system to function in a pro-tumor capacity by releasing cytokines and chemokines. We have identified the signaling adaptor protein, insulin receptor substrate-1 (IRS-1), as a key regulator of cytokine and chemokine production in lung cancer cells. The goal of this project is to determine the mechanisms by which IRS-1 regulates cytokine/chemokine production in cancer, and to identify key steps in this process that would represent therapeutic targets.
| Mark, Nicholas M; Kargl, Julia; Busch, Stephanie E et al. (2018) Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer. Am J Respir Crit Care Med 197:325-336 |
| Roh-Johnson, Minna; Shah, Arish N; Stonick, Jason A et al. (2017) Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo. Dev Cell 43:549-562.e6 |
| Kargl, Julia; Busch, Stephanie E; Yang, Grace H Y et al. (2017) Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun 8:14381 |
| Metz, Heather E; Kargl, Julia; Busch, Stephanie E et al. (2016) Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma. Proc Natl Acad Sci U S A 113:8795-800 |
| Busch, Stephanie E; Hanke, Mark L; Kargl, Julia et al. (2016) Lung Cancer Subtypes Generate Unique Immune Responses. J Immunol 197:4493-4503 |
