Understanding mechanisms of immunoevasion by precancer stem cells for breast cancer interception

About This Grant

SUMMARY Basal-like breast cancer (BLBC) is an aggressive cancer subtype that disproportionally affects younger women and women of African ancestry, contributing to cancer disparity. Additionally, women with BRCA1 germline mutations have an extremely high risk of developing BLBC. BLBC precancer tends to be high-grade and likely to progress to malignant cancer. Understanding immune escape mechanisms in BLBC precancer is crucial for developing immunoprevention strategies to intercept its progression to aggressive breast cancer. Recent studies have showed that the generation of embryonic multipotent stem-like cells (referred to as pre-CSCs) through de- differentiation is critical for BLBC precancer progression in mouse models. Importantly, de-differentiation to multipotent cells has also been observed in patients with germline BRCA1 mutations. Similar de-differentiation processes occur in other breast cancer subtypes, suggesting a broad strategy for cancer prevention by targeting pre-CSCs. However, how pre-CSCs escape immunosurveillance remains poorly understood. In our preliminary studies, we have discovered that BLBC pre-CSCs express high levels of the stem cell transcription factor SOX9, which greatly induce the expression of the immune checkpoint B7x (also known as B7-H4, B7S1 or VTCN1). These cells also upregulate multiple cancer testis antigens. We found that the SOX9- B7x pathway is necessary for inhibiting T cell infiltration and protecting pre-CSCs from T cell-mediated elimination. SOX9 or B7x knockout blocks the progression of BLBC precancer. These findings strongly support the hypothesis that BLBC pre-CSCs are unexpectedly immunogenic due to upregulation of cancer testis antigens, and the upregulation of immune checkpoint B7x by stem cell factor SOX9 in these cells are required for establishing an immuno-suppressive microenvironment crucial for safeguarding pre-CSCs from immune elimination. This hypothesis will be tested by pursuing the following specific aims: (1) Dissect the mechanisms by which SOX9 regulates B7x and other immunosuppressive pathways in in precancer stem cells; (2) Determine the mechanistic interactions between precancer stem cells and their reactive immune cells; and (3) Develop anti- B7x therapy, either alone or in combination, as new immunoprevention strategies targeting pre-cancer stem cells in breast cancer. The most effective strategies will be further tested in mouse models of other breast cancer subtypes. To accomplish our goals, we have generated a number of novel tools and resources. The outcomes of this project will elucidate new immunosuppressive mechanisms of pre-CSCs and develop anti-B7x therapy, either alone or in combination, as immunoprevention approaches against breast cancer.