Abstract 2354: Insulin receptor substrate-1 regulates immune cell content in lung adenocarcinoma
Authors: Metz Heather , Busch Stephanie E. , Kargl Julia , Hanke Mark L. , Kim Kyoung-Hee , Houghton A. McGarry 
Published: August 2015

Lung cancer is the leading cause of cancer deaths worldwide. In the United States, lung cancer accounts for ∼160,000 deaths per year while the five-year survival rate remains stagnant at ∼15%. A better understanding of the pathobiology for this disease is imperative for development of novel therapeutics to improve mortality rates. Lung adenocarcinoma (ADCA) accounts for over 50% of non-small lung cancer cases. Within this subset, K-ras is the most common activating mutation accounting for ∼35% of cases. Our group previously showed that K-ras activation generates an inflammatory response in lung tumors, mediated largely through the increased production of CC/CXC chemokines by tumor cells. The corresponding influx of neutrophils increased tumor growth, which was associated with degradation of the intracellular protein insulin receptor substrate-1 (IRS-1). Since IRS-1 is generally thought of as a pro-tumor entity, we decided to undertake a controlled study to further elucidate its pro-host role. We performed a study using a well-annotated human lung ADCA TMA (n = 136) and found that positive IRS-1 staining provided a 75-month median survival advantage among all cases (p = 0.01) and an 81-month median advantage within the K-ras subtype (p = 0.006). EGFR and non-K-ras/non-EGFR cases did not display differences. To further dissect the role of IRS-1 in tumor growth we generated LSL-K-ras/IRS-1fl/fl mice and studied them over a time course. LSL-K-ras/IRS-1-/- mice displayed highly significant early mortality (p&lt;0.0001) and increased tumor burden when compared to LSL-K-ras/IRS-1+/+ controls (p&lt;0.01). Surprisingly, IRS-1 loss in tumor cells generated a robust immune response. The bronchial alveolar lavage fluid of LSL-K-ras/IRS-1-/- mice had increased infiltration of macrophages (∼2.5x), neutrophils (∼40x) and lymphocytes (∼5x). Significant increases in many immune cell-recruiting chemokines were observed in the LSL-K-ras/IRS-1-/- mice compared to controls. Many cancers are able to manipulate the host immune response through signaling pathways that interface with IRS-1, including: phosphoinositol 3-kinase (PI3K), extracellular signal regulated kinase (MEK/ERK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT). An array of IRS-1 silenced A549 cells versus controls displayed no change in CC/CXC chemokine production. Evaluation of the tumor microenvironment, however, provided evidence for a role for IL-17 and IL-22 producing cells, which are present at tumor sites in human lung cancer cases and LSL-K-ras mice. We found that loss of IRS-1 increases pSTAT3 production in vivo and in vitro in the presence of IL-22, triggering chemokine release and the generation of a pro-tumor immune response. This is the first description of a pro-host role for IRS-1 in human cancer. This study provides an important marker in a subset (K-ras) of lung ADCA with a very poor prognosis that may be susceptible to JAK/STAT antagonism.

Citation Format: Heather Metz, Stephanie E. Busch, Julia Kargl, Mark L. Hanke, Kyoung-Hee Kim, A. McGarry Houghton. Insulin receptor substrate-1 regulates immune cell content in lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2354. doi:10.1158/1538-7445.AM2015-2354