Abstract 5394: Tumor-induced immunological changes in peripheral blood of untreated stage IV non-squamous NSCLC patients
Authors: Heuvers Marlies E. , Muskens Femke , Bezemer Koen , Lambers Margaretha , Dingemans Anne-Marie , Groen Harry , Smit Egbert , Hoogsteden Henk , Hegmans Joost , Aerts Joachim 
Published: August 2012

Abstract
Background Lung cancer is the most common cause of cancer mortality world wide. The five-year survival rate of stage III and IV non-small cell lung cancer (NSCLC) is poor with 16%. There is growing evidence that the immune system plays a paradoxical role in the development and progression of lung cancer. It influences tumor incidence, tumor growth, response to therapy, and the prognosis of the disease. Mouse models show that myeloid-derived suppressor cells (MDSCs) play a role in these processes. MDSCs are a heterogeneous population of immature myeloid cells and myeloid progenitor cells, which are present in the tumor micro-environment and the peripheral circulation of cancer patients. These cells are able to suppress features of immune responses, like T-cell proliferation and cytokine production. Aim In the present study we want to determine the role of pivotal immunological populations such as CD4+ T-cells, CD8+ T-cells, and MDSCs. Methods Fresh blood of 60 stage IV non-squamous-NSCLC patients and 15 healthy controls (HC) was studied. Mononuclear cells were purified from peripheral blood by density gradient centrifugation and analysed by flowcytometry. MDSCs were characterized as CD11b, CD15 CD33 positive and low expression of HLA-DR and CD16 cells. Suppressive activity of MDSCs was measured by CD3α-chain expression assays, and reactive-oxygen species (ROS) production using flowcytometry. Also T-cell proliferation assays were performed, in which sorted MDSCs were co-cultured with activated CD8-T-cells to investigate whether the MDSCs could inhibit the T-cell proliferation. Results All patients had a significantly increased MDSC population compared to healthy controls (p = 0.0009). Peripheral blood fractions possessed strong immunosuppressive functions, as shown by a high ROS production by MDSC, a decreased CD3α-chain expression in T cells compared to HC. In addition, the CD8+ T-cells showed no proliferation when co-cultured with MDSCs, indicating that MDSCs could block CD8+ -T cell proliferation. The populations of CD4+ T-cells and CD8+ T-cells were significantly decreased in lung cancer patients compared to healthy controls (p = 0.01 and p = 0.0024, respectively). Conclusion Circulating MDSCs are significantly increased, while CD4+ T-cells and CD8+ T-cells are significantly decreased in stage IV non-squamous-NSCLC patients compared to controls. MDSCs suppress the immune system by ROS production, down regulating the CD3α-chain expression and thereby inhibiting T-cell proliferation. This suggests that MDSCs may play an important role in disease progression and overall survival. Therefore, further investigation is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5394. doi:1538-7445.AM2012-5394