Enhancing triple negative breast cancer response to immune checkpoint inhibitor therapy via targeted therapies

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Project Summary Triple negative breast cancer (TNBC) is a subtype of breast cancer that is aggressive and difficult to treat, with limited treatment options beyond traditional chemotherapy. Given the recent approval of treatment of TNBC with the immune checkpoint inhibitors, anti-PD1 and anti-PDL1, combined with nab-paclitaxel, we are evaluating strategies that prime tumors to be more responsive to immune checkpoint inhibitors (ICI). Overactivation of the PI3K/AKT pathway is implicated in about 23.7% of TNBC tumors and is known to contribute to the maintenance of an immunosuppressive tumor immune microenvironment (TIME). This proposal will investigate the hypothesis that pan-AKT inhibition (AKTi) will enhance the efficacy of treatment with existing immune checkpoint inhibitors in some but not all preclinical models of TNBC, including mouse models and patient-derived organoid models. Experiments proposed in aim 1 will investigate how pan-AKTi affects the TIME when used in conjunction with anti-PD-1, anti-CTLA4, and a combination of anti-PD-1 + anti-CTLA4 (ICI). In vivo murine studies will be performed in AKTi responsive PYMT tumors and AKTi non-responsive EO771, 4T1, and 6DT1 tumors. Multi- color flow cytometry will allow detailed immunophenotyping of tumor and peripheral sites such as blood,lymph node, and spleen. Additionally, In vitro studies with T-cells will explore the mechanisms through which AKTi may enhance ICI efficacy as well as mechanisms of resistance to AKTi. In aim 2, a high throughput screen will be used to identify potential candidate drugs that enhance T cell-mediated tumor cell killing and therefore have the potential to enhance the efficacy of existing immune checkpoint inhibitors. A number of pan-AKT inhibitors as well as candidate drugs identified in the screen will be evaluated in patient-derived organoid models established from TNBC patients undergoing surgical resection. We will look for synergism between AKTi with immune checkpoint inhibition, evaluating direct AKTi-mediated tumor cell killing and immune-mediated tumor cell killing. These studies will enhance our understanding of mechanisms of response and resistance to AKTi in TNBC and the role of AKT inhibition in priming the tumor immune environment to enhance response to immune checkpoint inhibitors. We will identify alternative inhibitors that enhance TNBC response to ICI for those tumors that do not respond to AKTi. By examining the response of these therapies in organoid models of human TNBC, we will be able to predict parameters of response to therapy in a heterogenous population of TNBC patients.