Abstract 3182: Reduced tumor burden and mortality in IL-17RA-deficient EGFR mutant mice
Authors: Hanke Mark L. , Busch Stephanie E. , Kargl Julia , Kim Kyoung Hee , Houghton A McGarry 
Published: August 2015

Lung cancer is the leading cause of cancer death in the United States, with the five-year survival rates currently around 15%. Resistance to cancer therapies, like those that target epidermal growth factor receptor (EGFR), is an important clinical problem. The most common mechanism of resistance to targeted therapies in EGFR-mutant lung cancer is the T790M mutation. Given the lack of efficacy of the targeted therapy combinations tested so far, the ideal partner to an EGFR targeted therapy may be a drug that acts by an entirely different mechanism, possibly one that targets the tumor microenvironment. To dissect the role of the tumor microenvironment in lung cancer pathology we utilized mice engineered to express the L858R activating mutation within EGFR (TetO-EgfrL858R;Ccsp-rtTA) or the T790M resistance mutation (TetO-EgfrL858R/T790M;Ccsp-rtTA). Previous studies from our group indicate that KRAS mutant NSCLC is associated with a robust inflammatory response characterized by infiltrating immune cells, particularly macrophages and neutrophils. Neutrophils, which require IL-17 for recruitment and T cell suppression, promote tumor growth; and the infiltration of Th17 cells in human cancers is associated with a poor prognosis, making IL-17 an attractive therapeutic target for NSCLC.

Activation of the L858R or the T790M Egfr mutation within the lung was characterized by an abundant infiltration of alveolar macrophages, 8- and 14-fold increases respectively. In contrast, the number of neutrophils and CD8 T cells remained relatively unchanged after the expression of either Egfr mutation. In addition, the few CD8 T cells that were present within the tumor microenvironment appeared to exhibit a more exhausted phenotype within mice expressing the T790M mutation. The lack of expanded CD8 T cell number was also observed in a limited number of human EGFR lung specimens (n = 3). EGFR activation did however result in amplified numbers of both T regulatory cells and IL-17 producing T cells. Increased expression of the IL-17 differentiating cytokines TGF-β and IL-6, as well as the Th17 proliferative cytokine IL-1β was also observed by qRT-PCR gene expression analysis within L858R EGFR mutant mice. To further dissect the role of IL-17 in tumor growth TetO-EgfrL858R;Ccsp-rtTA mice were crossed to IL-17RA deficient mice. IL-17RA deficient EGFR mutant mice displayed enhanced survival and decreased tumor burden when compared to IL-17RA sufficient controls. IL-17RA loss also resulted in a less robust immune response within EGFR mutant mice as the bronchial alveolar lavage fluid showed decreased infiltration of macrophages, neutrophils and lymphocytes. Further examination of EGFR mutant lung tissue displayed alterations in immune cell-recruiting chemokines and cytokines after the loss of IL-17RA. Taken together, our data demonstrate a role for IL-17 in EGFR mediated lung tumorigenesis and suggest the use of IL-17 antagonism as a possible therapy for EGFR patients.

Citation Format: Mark L. Hanke, Stephanie E. Busch, Julia Kargl, Kyoung Hee Kim, A McGarry Houghton. Reduced tumor burden and mortality in IL-17RA-deficient EGFR mutant mice. [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 3182. doi:10.1158/1538-7445.AM2015-3182