Abstract
Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.
Highlights
Identified based on the ability of a small, phenotypically pure population of cancer cells to form heterogeneous tumors composed of diverse cell progeny, stem-like tumor cells have been identified in numerous solid and hematological cancer types [1]
We show that ALDHbright cancer stem cell (CSC) from several solid tumor types, including human primary tumors are sensitive to induction of natural killer (NK) ligands MICA and MICB following bortezomib treatment
We demonstrated the presence of a subpopulation of ALDHbright, stem-like tumor cells, which appear relatively resistant to the direct cytotoxic effects of the proteasome inhibitor bortezomib, but demonstrate upregulation of NK ligands and death receptors, which allow for additive anti-tumor effects when bortezomib pre-treatment is followed by NK immunotherapy in vitro and in vivo
Summary
Identified based on the ability of a small, phenotypically pure population of cancer cells to form heterogeneous tumors composed of diverse cell progeny, stem-like tumor cells have been identified in numerous solid and hematological cancer types [1]. The first published reports of tumor initiating cells were based on the isolation of CD34+ hematopoietic cells from blood samples of acute myeloid leukemia patients, which, once purified based on cell surface phenotype, were able. Cancer stem cells (CSCs) have been challenging to phenotypically categorize, multiple studies have relied on the expression and/or co-expression of specific cell surface and intracellular proteins in a variety of tumor models. A major challenge in the study of CSCs is the lack of a reliable, uniform, and practical marker system which can be used to identify and phenotype CSCs across different tumor types [4]. The activity and expression of the family of intracellular enzymes known as aldehyde dehydrogenases (ALDH) is one of a select few cellular constituents that has been found to reproducibly correlate with a CSC phenotype across tissue types [5,6]
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