Cancer stem cell-mediated immune escape.

Institution: University of California, Riverside
Investigator(s): Kuan-Hui Chen, M.S. -
Award Cycle: 2017 (Cycle 23) Grant #: 23IB-0005 Award: $187,500
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2017)

Non-technical overview of the research topic and relevance to breast cancer: It is only relatively recently that we have understood the importance of tumor-immune interactions in the development and progression of breast cancer. Even more recently, immunotherapy has been added to the armory of possible therapeutic interventions. The survival of cancer stem cells, which are difficult to kill for a variety of reasons, is a likely cause of breast cancer recurrence. This project will address how breast cancer stem cells evade immune cell killing. Cancer stem cells represent a small percentage of the overall tumor population and have characteristics similar to normal stem cells. Little is known about how breast cancer stem cells escape immune attack and whether by their presence they also limit immune cell killing of bulk tumor cells. We hypothesize that cancer stem cells secrete small immunosuppressive molecules that not only allow their own survival, but also prevent killing of bulk tumor cells. Our preliminary results have shown that breast cancer stem cells indeed secrete immunosuppressive molecules to allow them to evade the immune system. These are small molecules made of components known as nucleotides that are able to suppress an extremely strong activation of immune cells; adding these nucleotides to a tumor cell killing assay suppressed the ability of immune cells to kill both breast cancer stem cells and bulk tumor cells. Thus, in cancer patients, it seems likely that these nucleotides suppress the killing of both cancer stem cells and bulk tumor cells.

The question(s) or central hypotheses of the research: 1) What are the small immunosuppressive nucleotides secreted by breast cancer stem cells? 2) How do these small immunosuppressive nucleotides protect both breast cancer stem cells and the bulk tumor cells?

The general methodology: We will use a commercial kit that will identify what the small nucleotides are. The immune suppressive function of these nucleotides will be validated using a cancer cell killing assay in which strongly activated immune cells will be cultured together with cancer stem cells or bulk cancer cells in the absence or presence of each identified small nucleotide. The mechanism of action of these nucleotides will be tracked using fluorescent probes to detect how they enter cells and what they interact with inside immune cells.

Innovative elements of the project and potential impact: Our preliminary results have shown that breast cancer stem cells secrete immunosuppressive nucleotides. These small nucleotides in turn edit gene expression in immune cells resulting in inhibition of immune cell-mediated tumor clearance. The existence of such nucleotides has never before been recognized and so is a novel aspect of the tumor immunology paradigm. Through the proposed work, we can determine the identities of the immunosuppressive nucleotides and gain more knowledge about how these molecules modify immune reactions. Knowing their identity, it will be straightforward to design molecules that completely neutralize their action and allow immune destruction of cancer stem cells and clearance of cancer a cure. Production of these neutralizing molecules will then lead to preclinical and then clinical testing in patients with, or at risk of, metastatic disease.