Cells that enhance tumor growth and suppress anticancer immune attack are identified
Study results identified the population of white blood cells that tumors use to enhance growth and suppress the disease-fighting immune system. The results, which appeared in Immunity (2014; doi:10.1016/j.immuni.2014.10.020), mark a turning point in cancer immunology and provide the foundation for developing more effective immunotherapies.
For years, researchers have known that a diverse group of white blood cells called myeloid-derived suppressor cells (MDSC) are more abundant in cancer patients than in healthy persons. The cells enhance cancer growth and suppress the specialized T cells that target and destroy tumor cells.
MDSCs have a common origin in the bone marrow, but leave to travel throughout the body and become immune cells with different functions. Blocking T cells is one of the main MDSC functions.
Until now, however, efforts to distinguish among the cell types and identify the population responsible for antitumor immune suppression have fallen short. The puzzle has hampered efforts to harness the immune system to fight disease.
Working in the laboratory and in mouse models of cancer, researchers on this study, led by St. Jude Children's Research Hospital scientists in Memphis, Tennessee, showed immune suppression associated with MDSCs is primarily the work of monocytes, a type of white blood cells. Monocytes give rise to macrophages that help clean up dead or damaged tissue, fight cancer, and regulate the immune response.
"We have identified the monocytic cells as the important cell to target, not only in cancer but possibly for treatment of autoimmune disorders [such as] rheumatoid arthritis or inflammatory bowel diseases where dampening the immune response could provide relief," said corresponding author Peter Murray, PhD, a member of the St. Jude departments of Infectious Diseases and Immunology.
"We also identified growth factors and other molecules essential to the survival and function of these monocytic cells. Targeting these molecules could lead to more precise approaches for controlling the immune response at the tumor site. This study marks a significant step in efforts to understand, develop, and optimize immunotherapies for treatment of cancer," he said.
Previous research had shown that switching off the MCL1 gene in bone marrow led to the death of granulocytes, but not monocytes, via apoptosis. Further, the protein FLIP was found to be a key regulator of both apoptosis and necroptosis, which are pathways that cells use to get rid of damaged, dangerous or unneeded cells. Selectively eliminating FLIP in mice resulted in an over-abundance of granulocytes and a reduction in monocytes and related cells.
In this study, researchers selectively eliminated MCL1 or FLIP to track how the loss of granulocytes or monocytes affected T cells in the laboratory and in mouse models of neuroblastoma and other cancers. The results showed that monocytic cells are primarily responsible for T cell suppression around tumors. Scientists are still determining the role of the granulocytes in tumors.
The work also provided new details of how FLIP, MCL1 and the MCL1-like protein A1 work together to ensure survival of the monocytic population of MDSCs.