Are Ovarian Cancer Stem Cells the Target for Innovative Immunotherapy?

Abstract: Cancer stem cells (CSCs), a subpopulation of cancer cells with the ability of self-renewal and differentiation, are believed to be responsible for tumor generation, progression, metastasis, and relapse. Ovarian cancer, the most malignant gynecological cancer, has consistent pathology behavior with CSC model, which suggests that therapies based on ovarian cancer stem cells (OCSCs) can gain a more successful prognosis. Much evidence has proved that epigenetic mechanism played an important role in tumor formation and sustainment. Since CSCs are generally resistant to conventional therapies (chemotherapy and radiotherapy), immunotherapy is a more effective method that has been implemented in the clinic. Chimeric antigen receptor (CAR)- T cell, an adoptive cellular immunotherapy, which results in apparent elimination of tumor in both hematologic and solid cancers, could be used for ovarian cancer. This review covers the basic conception of CSCs and OCSCs, the implication of epigenetic mechanism underlying cancer evolution considering CSC model, the immunotherapies reported for ovarian cancer targeting OCSCs currently, and the relationship between immune system and hierarchy cancer organized by CSCs. Particularly, the promising prospects and potential pitfalls of targeting OCSC surface markers to design CAR-T cellular immunotherapy are discussed here.

Keywords: cancer stem cells, ovarian cancer, epigenetics, tumor cell surface marker, immunotherapy, CAR 

INTRODUCTION

Cancer stem cells (CSCs, also named tumor-initiating cells [TICs] or tumor-propagating cells [TPCs]) are a small subsection of cancer cells which can self-renew and differentiate into heterogeneous tumor cells and are believed to be the culprit for tumor initiation, growth, and recurrence. Many CSCs have been identified from a variety of human tumors including brain cancer, melanoma, breast cancer, liver cancer, pancreatic cancer, colon cancer, prostate cancer, and ovarian cancer.^1,2 Epigenetics have been found to have crucial function in cancer development as researches continue, which connect cancer cellular states and the tumor microenvironment in a tumor. Among gynecologic malignancies, ovarian cancer is the second most common and the first cause of death but it has the highest mortality rate.³Unfortunately, the majority of ovarian cancer patients who have complete remission by surgery and chemotherapy will ultimately have the cancer reoccur. Ovarian cancer stem cells (OCSCs) have been identified for more than a decade, and many kinds of OCSCs are thought to exist due to the variety of ovarian cancer subtypes or/and the heterogeneity within a tumor, and many surface markers of OCSCs have been targeted for therapy. CSCs are universally resistant to chemotherapy and radiotherapy; hence, immunotherapy is a promising approach for the elimination of CSCs, and a lot of clinical data can support the immunotherapy. Chimeric antigen receptor (CAR)-T cells are reconstructed T cells, which can use the receptors attached to themselves that can specifically recognize the specific antigen on cancer cells, CAR-T cells do not depend on HLA to kill cancer cells. HLA deficiency is a way of immune evasion for some cancer cells. The chimeric receptor is a designed receptor on T cell which does not depend on the T cell existing receptor. Anti-CSC CAR-T cells have been reported in some types of cancers, such as prostate cancer,⁴ glioblastoma multiforme (GBM),⁵ nasopharyngeal carcinoma,⁶ and cholangiocarcinoma (CCA).⁷ To date, only one study using CAR-natural killer (NK) cells to target OCSCs in vitro has been reported in a tiny but significant step in this field.⁸ Targeting OCSCs to design CAR has the prerequisite of known antigens on OCSCs; hence, it is possible to construct CAR to combat ovarian cancer by targeting OCSCs. Based on the CSC model to explore ovarian cancers and the correlative epigenetic mechanism under this process, the current immunotherapies are reviewed here and the recapitulation of CAR-T cellular immunotherapy targeting OCSCs is also discussed in this context.

THE CONCEPTION OF CSCs AND OCSCs

CSCs are a subpopulation in a tumor which differentiate into CSCs and non-CSCs possessing self-renewal ability which can also survive in conventional therapy. They were first found in acute myeloid leukemia (AML) in 1997, termed as severe combined immunodeficiency (SCID) which can differentiate into leukemic blasts revealing the hierarchy organization of AML clone.⁹ They have the characterization resembling normal stem cells, that is, differentiation into themselves and progeny cells with a slow cycling states. Traditional gene model means that tumor is a mutation of single gene cell subset. Indeed, a tumor does not contain sole single tumor genome, instead comprises of multiple genomes that have heterogeneity. “Gene model” and “CSC model” are harmonized when synthesizing genetic diversity, non-genetic influences like epigenetic modification, and nontumor cell elements (tumor microenvironment) which are all involved in intratumoral heterogeneity.¹⁰ The origins of CSCs are putative by three theories: a normal stem cell, a normal committed progenitor cell, or a transit-amplifying cell which possesses limited differentiation potential and self-renewal capability similarity with a stem cell.¹¹

CSCs are at the helm of tumor hierarchy owning functional traits, unlimited self-renewal potential, quiescent or slow-cycling states, and increased resistance to conventional therapies, which contribute to tumorigenesis, recurrence, and metastasis.¹² The dormancy of CSCs can explain the undetectable persistence of a tumor for a period of time even though a patient responds clinically after therapy until malignancy relapse exists in primary or secondary tumor site.¹³ Plasticity of CSCs confers the reversible dynamic change between non-CSC state and CSC state mediated by tumor microenvironment and tumor niche which facilitates the intricacy and heterogeneity of a tumor.¹⁴ The theories involved in CSCs resulting in carcinogenesis include chemical carcinogenesis, infection, mutation, or epigenetic changes.¹⁵ Cancer is an ecosystem, where CSC is on the apex of the pyramid of this ecosystem that is controlled by intricate hierarchical organization of CSCs. The clinical significance of CSC refers to many fields including detecting prognostic outcome, chemoresistance, radiation resistance, dissemination/anoikis resistance, immune system evasion, dormancy, and field cancerization which enlarge the dimensionality of cancer research.¹⁴