Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells

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.

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism

“…Our laboratory has shown that ATPbinding cassette family member B5 (ABCB5) is preferentially expressed by tumor-initiating and therapy-resistant CSC subpopulations in diverse human malignancies, where it is also co-expressed with CD133 (18)(19)(20)(21)(22). Recently, ABCB5 was found to be highly upregulated in the ALDH bright CSC subpopulation in the human U-87 MG GBM cell line (23). Moreover, ABCB5 has been established as a key mediator of tumor growth, aggressiveness, and multidrug resistance (MDR) in malignant melanoma, colorectal cancer, hepatocellular, oral squamous and Merkel cell carcinomas, and ocular surface squamous neoplasia (18,21,(24)(25)(26)(27)(28).…”

New avenues for melanoma immunotherapy: Natural Killer cells?

“…With regards to innovative therapies, proteasome inhibition, which reduces MHC class I molecules expression, have been shown to upregulate MICA/B and death receptors on several solid tumour CSCs, enhancing NK cell‐mediated killing and tumour regression in vivo after NK cell adoptive transfer …”

“…125,126 With regards to innovative therapies, proteasome inhibition, which reduces MHC class I molecules expression, have been shown to upregulate MICA/B and death receptors on several solid tumour CSCs, enhancing NK cell-mediated killing and tumour regression in vivo after NK cell adoptive transfer. 127 Another field of active research is the development of mAbs specifically targeting CSC surface markers. Conventional mAbs may interact with CD16 on NK cells thus enhancing their capability to eliminate CSCs by boosting ADCC.…”

<p>A Review of MicroRNA in Uveal Melanoma</p>

“…CSCs have an ability of self-renew and can differentiate into all cell types of a specific carcinoma. 65 There are evidences that CSC is a key factor of UM metastasis, moreover, it is susceptible to NK cell cytotoxicity. 66,67 Joshi et al 68 reported that UM CSCs could synthesize NK cell regulatory miRNAs, including miR-181a, miR-146a, miR-20a, miR-223 and miR-155.…”