abstract: Induction of cytotoxic T lymphocytes against ovarian cancer-initiating cells.

Abstract

The majority of patients with stage III/IV ovarian carcinoma that respond initially to standard therapies ultimately undergo relapse due to the survival of small populations of cells with tumor-initiating potential. These ovarian cancer-initiating cells (OCIC) are sometimes called cancer stem cells (CSC) since they express stem cell markers, and can survive conventional therapies such as chemotherapy, which usually target rapidly replicating tumor cells, and give rise to recurrent tumors that are more chemo-resistant and more aggressive. Thus it would be desirable to develop a therapy that could selectively target OCIC and be used to complement the conventional therapies. In the present study, we isolated a subset of ovarian cancer cells with a CD44(+) phenotype in samples from patients with ovarian cancer that possess CSC properties including the formation of spheroids in culture, self-renewal and the ability to be engrafted in immune-compromised mice. We next explored the use of immunotherapy using fusions of dendritic cells (DC) and OCIC to specifically target the OCIC sub-populations. Fusion cells prepared in this way activated T cells to express elevated levels of IFN-γ with enhanced killing of CD44(+) ovarian cancer cells. We envision a combined approach where conventional therapies such as chemotherapy kill the bulk of tumor cells, whereas OCIC-reactive CTL target the resistant OCIC fraction. A combined therapy such as this may represent a promising approach for the treatment of ovarian cancer.