Inflammatory Signaling in the Tumor Microenvironment
We associate 'inflammation' with diseases such as arthritis, inflammatory bowel diseases, bronchitis or rashes. Most of us would not consider cancer as an inflammatory disease, yet pathologists first made the link between cancers and inflammatory cells a century ago. Today, there is tremendous interest in cancer and inflammation because of the possibility that inflammation is helping cancer cells survive and proliferate. We study a special cell of the immune system called macrophages. Macrophages get their name from the Greek: 'big eater', and are important for many aspects of immunity: macrophages recognize and eat bacteria and viruses as well as dead and dying cells that need to be removed. Macrophages also signal to other cells of the immune system and help organize immune responses. However, macrophages can also become uncontrolled: over-active macrophages can cause excessive inflammation, and become unresponsive to other immune cells that give a 'stop' signal to block macrophages' aggressive behavior. Macrophages also invade tumors, often in large numbers. What are the macrophages doing in tumors: are they helping the cancer cells to grow? Or, do macrophages recognize that the cancer cells are out of control and need to be stopped? The goal of this project is to understand what is special about cancer macrophages. We will focus on cancers of childhood, and use model systems that closely mimic human cancer and translate out findings to human macrophages isolated from childhood cancers.
A. Specific Aims. The aims of the Springboard were to provide funds to continue the unfunded work proposed in my NCI application.
B. Results. Two major directions of the project were taken. In the first, we investigated the development and function of myeloid derived suppresors in cancer. Second, the outcomes of this work were recently published in Immunity. (See below.)
Immunity: "Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways." Volume 41, Issue 6, p947–959, 18 December 2014
Cell Reports: "TNF Counter Balances the Emergence of M2 Tumor Macrophages" Volume 12, Issue 11, p1902–1914, 22 September 2015 (http://www.cell.com/cell-reports/fulltext/S2211-1247(15)00918-3)