NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype

Abstract

Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24+/CD44+, CD133+, and aldehyde dehydrogenasebright) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.

NK cells control breast cancer and related cancer stem cell hematological spread

“…These observations are in agreement with those previously reported in other human solid tumor experimental systems. [15][16][17]25 In Fig. 2, NK cells were activated with IL2 in vitro, whereas autologous and allogeneic NK cells were used as effectors without any activation in Table 1.…”

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…14 Recently, increasing evidence from preclinical and clinical studies supports the potential efficacy of NK cell therapeutics in multiple cancer types. 15-19 Clinical studies also showed a positive correlation between outcomes of the therapy and the dose of NK cells administered, prompting the development of effective methods to grow NK cell in vitro . 19,20 …”

“…22 NK cells expanded by the K562-mb21 feeder cell method are currently used in multiple clinical trials and preliminary results are showing highly encouraging clinical efficacy for leukemia relapse prevention after stem cell transplant. 15 Recently, the K562-mb21 cell based method was modified to a cell-free, PM21-particle based method for both ex vivo and in vivo specific expansion of NK cells which can eliminate some logistical and safety concerns while also retaining the benefits of the feeder-cell based expansion. 24,25 These significant breakthroughs made in regards to generating large doses of NK cells allow for their potential use as a viable and attractive therapeutic option for cancer treatment.…”

NK Cells in Cancer Immunotherapy

“…IL-2-and IL-15-activated NK cells were found to be cytotoxic against human breast cancer stem cells and CD 133+ melanoma CSCs [90]. Recently, Ames et al [91] showed that NK cells kill CSCs from diferent kinds of tumors, through the interaction of the NKG2D activating receptor with its ligand (MICA/B). …”