Infiltration of immunosuppressive CD4+CD25+CD127low/-FOXP3+ regulatory T cells (Tregs) into breast tumors is associated with an invasive phenotype and poor prognosis. Treg accumulation is particularly prominent in claudin-low breast cancer, an aggressive subtype that is usually characterized by the triple-negative receptor status. Better understanding of the mechanisms responsible for Treg accumulation in breast tumors is of the utmost urgency, and the ability to inhibit intratumoral Treg accumulation and/or activity has an enormous therapeutic potential. The long-term goal of our research is to elucidate the immunosuppressive mechanisms in breast tumor microenvironment and to use this knowledge to improve immunotherapies for breast cancer. The objective of this pilot grant is to test whether ADAM12, a member of the ADAM family of cell surface metalloproteases, plays a role in immunosuppression using the T11 orthotopic transplantation mouse model of claudin-low breast cancer. Our central hypothesis is that ADAM12 promotes Treg accumulation in T11 tumors and/or potentiates the suppressive function of tumor- infiltrating Tregs. To test our hypothesis, we will pursue the following Specific Aims: 1. Determine the effect of ADAM12 knockout in T11 cells on the number of tumor-infiltrating Tregs in the T11 orthotopic transplantation mouse model of claudin-low cancer. 2. Examine the role of ADAM12 in regulating the suppressive function of Tregs in T11 claudin-low tumors. Our studies are significant because they may identify key mechanisms controlling immunosuppression in breast cancer and lay groundwork for the development of highly selective anti-Treg strategies. The proposed research is innovative because, for the first time, it will address a possible role of ADAM12, a breast tumor cell-specific protease, in regulating Treg accumulation and/or function in the tumor microenvironment.
The expected outcome of our studies is the identification of a novel mechanism contributing to immunosuppression in the breast tumor microenvironment. Therefore, our results may have a significant impact on current and future immunotherapies for breast cancer.