Immune cell activity may help predict breast cancer response to neo-adjuvant chemotherapy

"By tracking the levels of these immune cells and correlating these levels to chemotherapy response, we're hoping to give physicians a solid biomarker that can predict which patients will be more likely to benefit from neo-adjuvant chemotherapy," says oncologist Robert Wesolowski, MD, of The Ohio State University Comprehensive Cancer Center and James Hospital.

Of the approximately 230,000 women who will be diagnosed with breast cancer this year, many will receive chemotherapy in an attempt to shrink or kill tumors before breast surgery. Research suggests that women whose cancer responds to this early treatment have higher survival rates than those with a poor response.

Wesolowski, who received a Davis/Bremer Pilot Award from Ohio State's Center for Clinical and Translational Science (CCTS) to conduct his research, felt that the response could be related to the levels of circulating myeloid derived suppressor cells.

Discovered about fifteen years ago, MDSCs are produced in the bone marrow in response to cancer derived factors. MDSCs can inhibit the immune response against cancer cells by inhibiting the activity of cytotoxic T-cells, which not only help fight infections, but can also develop into powerful cancer killers. Wesolowski says some cancer cells are able to manipulate the way MDSCs behave so that tumors can grow unchallenged and unnoticed by the immune system.

"Tumors produce chemical signals that prevent the MDSCs from maturing into fully differentiated immune cells such as dendritic cells and granylocytes. These immature MDSCs circulate in the blood stream, producing more chemical signals that convince the immune system to overlook cancer cells," said Wesolowski. "Even if chemotherapy is killing tumor cells, it may not be enough to overcome an immune system already dysregulated by MDSCs."

Wesolowski, who also manages Ohio State's phase I trials for experimental solid tumor cancer therapies, was intrigued by the idea that MDSCs may undermine chemotherapy -- and in doing so, offer a quantifiable biomarker to predict response to treatment.

Under the mentorship of William Carson, MD, a nationally-recognized immunotherapy-cancer expert, Wesolowski decided to focus on granulocytic and monocytic MDSCs (two different subsets of MDSCs) to determine if one or both are related to response in women with breast cancer treated with pre-operative chemotherapy. Wesolowski's team studied women with operable breast cancer and measured the amount of both types of MDSCs in their blood stream before and after neo-adjuvant chemotherapy treatment.

Initial results indicate that women who had lower levels of granulocytic MDSCs in their bloodstream at the end of chemotherapy treatment were more likely to have had a complete response to therapy -- meaning that their tumors were undetectable. Women whose granulocytic MDSCs levels were high at the end of chemotherapy were more likely to have residual disease at the time of surgery. In contrast to granulocytic MDSCs, Wesolowski found that monocytic MDSCs remained at consistently low levels, potentially indicating that they may not play a role in pre-operative chemotherapy response -- an outcome that Wesolowski says will need to be investigated further.

Wesolowski also emphasizes that his study is very preliminary and is not looking to evaluate association between MDSC levels and survival outcomes. However, his work sets the stage for several different types of exploration around the critical immune cells and chemotherapy.

"Could we pre-emptively reduce the amount of circulating MDSCs before chemotherapy and improve response? Could we discover that certain chemotherapies will work better even when there is a high-level of MDSCs? Could MDSCs be used to provide an objective measurement of response across the duration of therapy to reassure patients and physicians that the intervention is working? It really opens the door to some exciting possibilities," said Wesolowski.

Carson agrees that a biomarker that could identify best candidates or give clinicians a way to evaluate therapy efficacy during treatment would change the way that neo-adjuvant chemotherapy is currently used and viewed.

"Neither patients nor physicians want to lose valuable time and resources on an ineffective treatment, and sometimes we are confronted with that," said Carson, who is the principal investigator on a National Cancer Institute (NCI) funded study looking at MDSCs within Ohio State's Innate Immunity research program. "Knowing in advance which patients are more likely to benefit from early chemotherapy or being able to monitor the efficacy of the intervention in real time would transform how chemotherapy is used."

Wesolowski is currently analyzing the data from his study, and hopes to present his findings at upcoming medical meetings. His team is planning on conducting additional studies with the collected blood to characterize the presence of other immune cells such as tumor associated macrophages, as well as other influences from the tumor micro-environment that may manipulate the immune response. A K12 award from the NCI is also helping him research drugs that may block certain receptors on the surface of MDSCs, possibly preventing cancer cells from disrupting their function.

"Cancer has evolved to become very good at subverting the body's natural immune responses, but we're getting better at reading the clues it gives us, and we're getting better at stopping it, too, " said Wesolowski.

Wesolowski would like to acknowledge his collaborators on the study, including Meghan Dugan, who performed the laboratory part of this research, such as the flow cytometry, and Kayla Levine who is the lab manager in Carson's Laboratory and who was critical in coordinating blood sample collection and procurement.