Abstract 634: Combination chemotherapy significantly reduces indoleamine 2,3-dioxygenase activity in NSCLC patients

Abstract

Abstract Heterogeneity and immunosuppression in the tumor microenvironment (TME) has dampened the efficacy of current frontline combination chemotherapies for lung cancer which has provided limited improvement in patient survival. Modified amino acid metabolism in the TME contributes to lung cancer progression and suppression of anti-tumor immunity. Enhanced tryptophan metabolism in primary lung cancer patients is indicative of advanced disease stage. One of the key regulators of tryptophan metabolism is an intracellular, heme-containing enzyme indoleamine 2,3-dioxygenase (IDO). IDO catabolizes the breakdown of tryptophan into a toxic, immunosuppressive metabolite, L-Kynurenine (L-Kyn). Induction of IDO and accumulation of its metabolite correlates with poor prognosis and overall patient survival. We hypothesized that IDO enzymatic activity would be elevated in lung cancer patients compared to normal healthy controls. We predicted that combination chemotherapy strategies would modulate serum levels of L-Kyn and IDO activity in the immune compartment of lung cancer patients. Using an IDO enzymatic activity assay to measure the production of L-Kyn, we demonstrate that prior to receiving combination chemotherapies, Non-Small Cell Lung Cancer (NSCLC) patients (n=11) display significantly elevated levels of this immunosuppressive serum metabolite compared to healthy relatives (n=8) (Student's t-test p=0.000087; Paired Means p=0.0001). Following the second cycle of treatment, serum L-Kyn was reduced significantly (Student's t-test p=0.023; Paired Means p=0.043) in a subset of patients (n=3 of 5) suggesting response to chemotherapy, but these post-treatment levels remained elevated overall compared to healthy relatives. Additionally, greater levels of IDO enzymatic activity were observed in circulating immunosuppressive myeloid-derived suppressor cells from NSCLC patients and peripheral blood mononuclear cells prior to receiving combination chemotherapy compared to those from healthy relatives. These preliminary studies suggest that the IDO enzymatic pathway and tryptophan metabolism may serve as important therapeutic targets and diagnostic markers in predicting clinical outcomes of combination chemotherapies in the treatment of NSCLC in humans. Citation Format: Cara C. Schafer, Yong Wang, Anandi Sawant, Tong Huan Jin, Selvarangan Ponnazhagan, Stefan C. Grant, Jessy S. Deshane. Combination chemotherapy significantly reduces indoleamine 2,3-dioxygenase activity in NSCLC patients. [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 634. doi:10.1158/1538-7445.AM2014-634