Donkor Moses K, Lahue Elaine, Hoke Traci A, Shafer Laura R, Coskun Ugur, Solheim Joyce C, Gulen Dumrul, Bishay John, Talmadge James E
Laboratory of Transplantation Immunology, Department of Pathology and Microbiology, 987660 Nebraska Medical Center, Omaha, NE 68198-7660, USA.
Int Immunopharmacol. 2009 Jul;9(7-8):937-48. doi: 10.1016/j.intimp.2009.03.021. Epub 2009 Apr 9.
The tumor microenvironment is heterogeneous for the expansion and infiltration by myeloid derived suppressor cells (MDSCs) which has been hypothesized to be dependent on tumor burden. We report a relationships between tumor size, MDSCs and T-cells; using four murine mammary tumors to assess tumor growth, infiltration and gene expression. Our analysis of cellular infiltration into tumors and gene expression used collagenase dissociated tumors and density gradient isolation of non-parenchymal cells (NPCs). The frequency of splenic and peripheral blood (PB) MDSCs was tumor dependent resulting in a significantly increased number of MDSCs. The MDSC frequency inversely correlated with the frequency of CD3+ lymphocytes in the spleen, independent of the tumor studied and directly correlated with tumor burden. Tumor growth up-regulated cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), granulocyte (G-) and granulocyte-monocyte-colony stimulating factor (GM-CSF), arginase-1 (ARG-1), and nitric oxide synthase-2 (NOS-2) transcription in the tumor and spleens (not VEGF-A). The frequency of splenic MDSCs directly correlated with splenic COX-2, NOS-2, and ARG-1 message levels, while COX-2 and NOS-2 transcript levels inversely correlated with splenic CD3+ cell frequency. COX-2 mRNA levels also directly correlated with the ARG-1 and NOS-2 transcript levels from tumor-infiltrating leukocytic cells, supporting prostaglandin E2 as a regulator of ARG-1 and NOS-2 transcription. In summary, MDSC numbers in the spleen and tumor microenvironment are tumor dependent, directly correlating with tumor size and inversely correlating with T-cell number. MDSCs are also directly associated with VEGF-A and G-CSF transcript levels suggesting multiple mechanisms for MDSC regulation and COX-2, NOS-2 and ARG-1 supporting multiple mechanisms of T-cell suppression.
肿瘤微环境对于髓源性抑制细胞（MDSCs）的扩增和浸润而言是异质性的，据推测这取决于肿瘤负荷。我们报告了肿瘤大小、MDSCs和T细胞之间的关系；使用四种小鼠乳腺肿瘤来评估肿瘤生长、浸润和基因表达。我们对肿瘤细胞浸润和基因表达的分析使用了胶原酶解离肿瘤以及非实质细胞（NPCs）的密度梯度分离法。脾脏和外周血（PB）中MDSCs的频率取决于肿瘤，导致MDSCs数量显著增加。MDSC频率与脾脏中CD3 + 淋巴细胞的频率呈负相关，与所研究的肿瘤无关，且与肿瘤负荷直接相关。肿瘤生长上调了肿瘤和脾脏中环氧合酶 - 2（COX - 2）、血管内皮生长因子 - A（VEGF - A）、粒细胞（G -）和粒细胞 - 单核细胞集落刺激因子（GM - CSF）、精氨酸酶 - 1（ARG - 1）以及一氧化氮合酶 - 2（NOS - 2）的转录（VEGF - A除外）。脾脏MDSCs的频率与脾脏中COX - 2、NOS - 2和ARG - 1的信使水平直接相关，而COX - 2和NOS - 2转录水平与脾脏CD3 + 细胞频率呈负相关。COX - 2 mRNA水平也与肿瘤浸润白细胞中ARG - 1和NOS - 2的转录水平直接相关，支持前列腺素E2作为ARG - 1和NOS - 2转录的调节因子。总之，脾脏和肿瘤微环境中的MDSC数量取决于肿瘤，与肿瘤大小直接相关，与T细胞数量呈负相关。MDSCs还与VEGF - A和G - CSF转录水平直接相关，提示MDSC调节的多种机制，而COX - 2、NOS - 2和ARG - 1支持T细胞抑制的多种机制。
