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 (OVCA)-initiating cells (OCIC) are sometimes called cancer stem cells (CSC) because 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 this study, we isolated a subset of OVCA cells with a CD44 1 phenotype in samples from patients with OVCA 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 and OCIC to specifically target the OCIC subpopulations. Fusion cells (FCs) prepared in this way activated T cells to express elevated levels of IFN-c with enhanced killing of CD44 1 OVCA cells. We envision a combined approach where conventional therapies such as chemotherapy kill the bulk of tumor cells, whereas OCIC-reactive cytotoxic T lymphocytes target the resistant OCIC fraction. A combined therapy such as this may represent a promising approach for the treatment of OVCA.Epithelial ovarian cancer (EOC) is responsible for the majority of gynecologic cancer deaths despite recent advances in adjuvant chemotherapy. Indeed, the majority of patients with Stage III/IV ovarian cancer (OVCA) that respond initially to standard therapies ultimately relapse due to drug-resistant disease refractory to further treatment with chemotherapy.

Cancer Stem Cell’s Potential Clinical Implications

“…Accordingly, Weng et al (24) demonstrated that fusion of dendritic cells (DCs) and ovarian CSCs resulted in the activation of T cells expressing higher levels of IFN-γ, with an increased killing power against CSCs. Glioma CSCs can also be targeted by cytotoxic T lymphocytes (CTL) through a perforin-mediated mechanism.…”

Immunotherapy in Colorectal Cancer

“…Although CSC is often resistant to a variety of treatments, including chemotherapy and radiotherapy, immunotherapy may still be effective [8][9][10] . A combined approach that uses conventional chemotherapy or radiation to kill the bulk of cancer cells and immunotherapy to keep residual CSCs and differentiated cancer cells in check may abrogate the replenishing pool of CRC cells [91] .…”

“…Thus, novel treatment modalities are needed. Interestingly, tumors that develop chemotherapy or radiation resistance are still suitable targets for immunotherapy [7][8][9][10] . Therefore, cancer immunotherapy may be effective for treating CRC patients and/or preventing relapse.…”

Production of corticotropin-releasing factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine

“…On day 6 of culturing, nonadherent and loosely adherent cells were collected and cultured in 100-mm tissue culture dishes (10 6 cells/mL; 10 mL/dish) for 30 min. Nonadherent cells were then removed and further enriched using the repeated adherence method to purify MoDCs [18] .…”

“…Moreover, low levels of UCN1 production were detected in E. coli-stimulated MoDCs, but this was not observed in a previous mouse study [27] . In this study, human MoDCs were generated using rhGM-CSF and rhIL-4, as previously described [18] . However, JAWS Ⅱ was generated with murine GM-CSF alone.…”