Role of mRNA stability in tumor-associated macrophages

Tumor invading immune cells are important factors during cancer development, controlling tumor incidence, growth, metastasis as well as tumor clearance by the host immune system before and after chemotherapy. In particular, tumor associated macrophages (TAMs) affect all stages of tumor development, being beneficial or detrimental depending on the mode of activation. TAMs thereby display a very distinct expression pattern, often suppressing the emergence of a proper anti-tumor immune response. Macrophages display a highly plastic expression pattern that is to a certain extent controlled at the level of mRNA stability. During inflammation, the decay of a broad set of inflammatory transcripts in macrophages is controlled by the mRNA binding protein Tristetraprolin (TTP), leading to the removal of both pro- and anti-inflammatory transcripts. TTP controls immune homeostasis and determines macrophage activity. TAMs express high levels of TTP suggesting a putative role of mRNA stability in shaping TAM activity. The laboratory of Peter Murray studies the function of TAMs in different mouse tumor models. He is especially interested, how the TAM transcriptome is shaped towards a pro-tumor environment. The suggested project aims to identify the influence of mRNA stability on cancer development by balancing inflammatory as well as anti-tumor responses in TAMs. TTP is known to dampen the production of pro- and anti-inflammatory proteins in macrophages leading to the hypothesis that increased TTP expression in TAMs might result in an altered macrophage activity within the tumor microenvironment. This hypothesis could provide a new mechanism, how cancer cells can evade the host immune surveillance.

Cancer development is accompanied by a finely tuned inflammatory reaction that supports tumor growth. In this research study I asked the simple question how the balance is kept between beneficial aspects of tumor inflammation like continuous supply with new nutrients and inflammatory reactions that are connected to an anti -tumor immune responses? Considering that the prognosis for cancer patients is highly dependent on whether the immune system supports tumor growth or can be reeducated to fight cancer, unrevealing the mechanisms that control immune cells in tumors is of prime importance for the development of future therapies. My proposal was therefore designed to investigate the role of Tristetraprolin (TTP), a protein well known to regulate the duration and magnitude of inflammation in macrophages which are among the most abundant immune cells found in cancer. During acute inflammation such as after bacterial infection, TTP decreases the production of a broad set of inflammatory mediators and initiates resolution of inflammation once the infection has been cleared. In macrophages isolated from tumors, we found TTP was highly produced, however its activity turned out to be counteracted by the chronic type of inflammation prevalent in the tumor microenvironment. Despite reduced activity, TTP was able to limit the production of a selected set of genes known to interfere with tumor growth. In summary, TTP was unable to resolve the inflammatory response elicited by macrophages because its activity was blocked by the continuous activation of inflammation in the tumor. However, the remnant TTP activity was sufficient to reduce the production of certain genes that would otherwise impair tumor growth. We could therefore show that TTP is an important regulator of tumor macrophages, keeping the balance between beneficial and detrimental tumor inflammation. Recent strategies to manipulate the host immune response to fight cancer by altering the global influx or survival of tumor infiltrating monocytes lead to severe side effects associated with the important functions of macrophages throughout the body. My data identified a pathway that can be exploited to fight cancer in a more surgical manner, altering tumor associated macrophages to specifically counteract tumor growth.