Dr. Huan-Hui (Ethan) Chen, PhD
Molecular and biophysical mechanisms of immune suppression by circulated metastatic cancer stem cells
One critical issue for cancer treatment is the existence of a rare cell population, cancer stem cells (CSCs), that drive the inexorable growth of malignant tumors, resist several types of treatments and render the opportunity for cancer recurrence following treatment and remission. Eradication of CSCs is therefore one of the major challenges of cancer therapy currently. In spite of increased interest and research in this field, our understanding of cellular and molecular mechanisms that underlie CSC properties is still very limited. To better tackle this population, our research work with a special focus on metastatic CSCs has identified three novel mechanisms that the circulated metastatic CSCs use to avoid immune surveillance. 1) Metastatic CSCs but not bulk tumor cells in response to the presence of activated T cells in the environment could release miRNAs which suppress both activation and proliferation of effector T cells. 2) Metastatic CSCs can recruit T regulatory cells through secretion of CCL5 and CCL17 and a physical interaction between CSCs and Tregs occurs once recruited. 3) Metastatic CSCs could determine the fate of macrophage polarization through the generation of an arginine metabolite, asymmetric dimethylarginine (ADMA), which leads macrophage polarization towards M2 end. In this proposal we will initially study whether secretion of immunoediting miRNAs by metastatic CSCs is a common thing in different molecular subtypes of breast cancers (Aim1). We will also study how effector T cells perceive the signals from these miRNAs, with our hypothesis through the intracellular toll-like receptors (Aim 1). In Aim 2, we will examine whether blockage of ccl17 and ccl5 with neutralizing antibodies prevents the recruitment of Tregs and the subsequent immune suppression that is driven by the recruited Tregs. Using a human protomicroarray, we will further identify proteins involved in the molecular interactions between CSCs and Tregs. Finally, in Aim 3 we will address the molecular mechanisms how ADMA is accumulated in the microenvironment by CSCs and how ADMA affects macrophage polarization through an effect on mitochondrial function. Thus, with the completion of this proposal, the information collected from this work will not only provide mechanistic insights of tumor progression mediated by metastatic CSCs to escape from immune surveillance but may also lead to more effective therapeutic interventions specifically for CSCs. In addition, it may also serve as a proof of-principle to support the development of therapeutic strategies for other types of cancers.