The role of immature myeloid suppressor cells (IMSCs) in transgenic mammary tumor chemoprevention and therapy by Celecoxib (49.21)

Abstract

Immune manipulation can control tumor initiation and growth while tumor growth may suppress host immunity. In our studies of tumor–host interactions, we observed a tumor associated expansion of IMSCs and suppression of T cell number and tumor infiltration. Further, the cyclooxygenase-2 (COX-2) inhibitor, Celecoxib had chemopreventative and as shown for the first time, therapeutic activity for mammary tumors in HER-2/neu transgenic BALB/c mice. Tumor growth was associated with a significant decrease in T cells and a significant increase in IMSCs (CD11b+Gr1+). In addition type 1 cytokine transcripts were depressed, while transcription levels of COX-2, arginase-1 (ARG1), nitric oxide synthetase-2 (NOS2), granulocyte (G) and G-monocyte colony stimulating factor, and vascular endothelial growth factor-alpha (VEGF-a) were increased in the preneoplastic lesions, tumors, and spleens and to a greater extent tumor infiltrating leukocytes. Celecoxib chemoprevention reduced the changes in IMSC and T cell numbers and cytokine and enzyme transcription levels. We posit that the increase in IMSCs may be due to the increased levels of COX-2, VEGF-a and growth factor(s), while the loss of T cell numbers and function maybe due to the heightened levels of ARG1 and NOS2. Further, as Celecoxib administration does not increase T cell infiltration of tumors or decrease IMSC infiltration, the changes in cytokine and growth factor levels maybe critical to the improved clinical outcomes. Together, these studies suggest an important role for IMSCs and its regulation by Celecoxib in cancer induction, and therapeutic intervention. Supported in part by funding from NIH grant 5 RO1 AT001739, Eppley Cancer Center and Nebraska DHHS LB506.