Abstract 4860: Insulin receptor substrate-1 regulates immune cell content in lung adenocarcinoma

Abstract

Abstract 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. One of the most common activating mutations in lung cancer is K-ras. Our group previously showed that K-ras activation generates an inflammatory response in lung tumors, mediated largely through the increased production of neutrophil chemokines by tumor cells. The corresponding increase in neutrophil recruitment in this model increased tumor growth, which was associated with degradation of the intracellular protein insulin receptor substrate-1 (IRS-1). A study of non-small cell lung cancer demonstrated that IRS-1 was low or absent in 46% of cases. To further dissect the role of IRS-1 in tumor growth we generated LSL-K-ras/IRS-1 fl/fl mice and subjected them to adenoviral cre. LSL-K-ras/IRS-1-/- mice displayed early mortality and increased tumor burden when compared to LSL-K-ras/IRS-1+/+ controls. Surprisingly, IRS-1 loss in tumor cells generated a robust immune response. The bronchial alveolar lavage fluid of LSL-K-ras/IRS-1-/- mice showed increased infiltration of macrophages, neutrophils and lymphocytes. Further examination of the chemokine profiles of LSL-K-ras/IRS-1-/- and LSL-K-ras/IRS-1+/+ mice showed a significant increase in many immune cell-recruiting chemokines in the LSL-K-ras/IRS-1-/- mice including CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCl12. 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). As some cytokines can activate IRS-1 via JAK/STAT signaling, we suspected that IL-17 and IL-22 might function in this regard. Loss of IRS-1 increases pSTAT3 production, which triggers chemokine release and the generation of a pro-tumor immune response. Preliminary data to support this hypothesis include: 1) presence of IL-17 and IL-22 producing cells (e.g. Th17) at sites of tumor in LSL-K-ras mice, 2) induction of pTyr-IRS-1 upon IL-17 and IL-22 stimulation in A549 cells, and 3) increased CC and CXC chemokines in IRS-1 deficient cells upon IL-17 and IL-22 stimulation. Experimentation is ongoing to further elucidate the mechanism behind this phenotype. Citation Format: Heather E. Metz, Stephanie E. Busch, Mark L. Hanke, Julia Kargl, Kyoung-Hee Kim, A McGarry Houghton. Insulin receptor substrate-1 regulates immune cell content in lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4860. doi:10.1158/1538-7445.AM2014-4860