Modulating myeloid derived suppressor cell function to alter response to checkpoint inhibition
MDSCs have been shown to play an important role in response or lack thereof to checkpoint inhibition in breast cancer. Our lab was a part of a collection of studies investigating how the histone deacetylase inhibitor entinostat alters MDSC suppressive function to promote response to checkpoint inhibitors anti-PD1 and anti-CTLA4. (2021, 2018) We are continuing this work to understand the mechanism of altered suppression through our investigation of the signaling pathways that control suppression such as STAT3 and NFkB. We are also investigating differences in MDSC function in lung metastases vs. primary breast tumors to determine if MDSC modulation is disease site specific.
Accounting for heterogeneity of the suppressive immune microenvironment according to tumor site
It has been shown that response to checkpoint inhibition may be correlated with site of disease. For example, patients with breast cancer with liver metastatic disease have been shown to have decreased responses vs. those with other metastatic disease. Through multiple modalities of analysis we are looking at differences in immunosuppressive cell types and functions according to metastatic sites such as the liver, brain and lung in both patients and mouse models of breast cancer.
Investigation of novel therapeutics targeting immunosuppressive cells
It is clear based on numerous clinical trials in breast cancer that single agent checkpoint inhibition is ineffective in patients with breast cancer. There is a need for novel combination therapies to improve response rates and clinical outcomes. Through exploratory analysis of single cell RNA sequencing in murine tumors treated successfully with immunotherapy, we have determined multiple immune cell targets that have the potential to be modulated and lead improved response rates. Ongoing projects in the lab are investigating agents that target these immune cells, such as myeloid derived suppressor cells, tumor associated macrophages and dendritic cells, and will explore mechanisms of response.
Racial disparities of the immune response in breast cancer
It has been shown that women of African American and Hispanic descent often have more aggressive disease and poorer outcomes. Differences in immune response to malignancy are likely to contribute to these outcomes and if better characterized can lead to a more personalized approach to clinical trial design and drug development. Ongoing projects in the lab are working to better understand these differences and thanks to the tremendous efforts of our patients and clinical research teams, we are actively working on analysis of patient samples to contribute to this increasingly important body of work.