Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

Wang, Bin; Wang, Qiang; Wang, Zhe; Jiang, Jun; Yu, Shanshan; Ping, Yi‐Fang; Yang, Jing; Xu, Senlin; Ye, Xian-Zong; Xu, Chuan; Yang, Lang; Qian, Cheng; Wang, Ji Ming; Cui, You‐Hong; Zhang, Xia; Bian, Xiu‐Wu

doi:10.1158/0008-5472.can-13-2563

Cited by 167 publications

(133 citation statements)

References 48 publications

(58 reference statements)

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“…It has recently been reported that human ALDH C CSCs, derived from human breast cancer, escape NK recognition by downregulating NKG2D ligands, thanks to the expression of miR20a. 33 Our data in mice expand this finding and indicate that not all breast cancer-derived CSCs are resistant to NK cell cytotoxic attack.…”

Section: Tumorspheres Derived From the Murine Erbb2supporting

confidence: 71%

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

et al. 2017

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The growth and recurrence of a number of cancers is driven by a scarce population of cancer stem cells (CSCs), which are resistant to most current therapies. It has been shown previously that natural killer (NK) cells recognize human glioma, melanoma, colon and prostate CSCs in vitro. We herein show that human and mouse breast CSCs are also susceptible to NK cytotoxic activity in vitro. Moreover, CSC induced autologous NK cell activation and expansion in vivo, which correlate with the inhibition of CSC metastatic spread. These data suggest that NK cells control CSC metastatic spread in vivo and that their use in breast cancer therapy may well be fruitful.

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Section: Tumorspheres Derived From the Murine Erbb2supporting

confidence: 71%

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

et al. 2017

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“…S1), and we did not observe any downregulation of the NKG2D receptor on TIML-NK cells secondary to tumor contact (data not shown). Together with the existing evidence that sustained exposure to NKG2D-L expressing tumor cells may indeed render NK cells dysfunctional, 45,46 our data do not support a significant contribution of the NKG2D-NKG2DL axis in the induction of tumor-induced memory NK cell formation. In addition, we were neither able to detect IL15 in our culture supernatants (data not shown) nor did we find any evidence for upregulated pSTAT1, three or five expression in TIML-NK cells (Fig.…”

Section: Discussionsupporting

confidence: 50%

Tumor-priming converts NK cells to memory-like NK cells

et al. 2017

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Fascinating earlier evidence suggests an intrinsic capacity of human natural killer (NK) cells to acquire adaptive immune features in the context of cytomegalovirus (CMV) infection or pro-inflammatory cytokine stimulation. Since the role of memory NK cells in cancer has so far remained elusive and adoptive NK cell transfer in relapsing pediatric acute B cell precursor leukemia (BCP-ALL) patients awaits improvement, we asked the question whether tumor-priming could promote the generation of memory NK cells with enhanced graft-vs.-leukemia (GvL) reactivity. Here, we provide substantial evidence that priming of naive human NK cells with pediatric acute B cell leukemia or acute myeloid leukemia specimens induces a functional conversion to tumor-induced memory-like (TIML)-NK cells displaying a heightened tumorspecific cytotoxicity and enhanced perforin synthesis. Cell cycles analyses reveal that tumor-priming sustainably alters the balance between NK cell activation and apoptosis in favor of survival. In addition, gene expression patterns differ between TIML-and cytokine-induced memory-like (CIML)-NK cells with the magnitude of regulated genes being distinctly higher in TIML-NK cells. As such, the tumor-induced conversion of NK cells triggers the emergence of a so far unacknowledged NK cell differentiation stage that might promote GvL effects in the context of adoptive cell transfer.

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“…However, the potential of immunotherapy for CSCs remains controversial [51]. Previous studies showed that breast CSCs had resistance to NK killing due to reduced expression of the ligands for NKG2D, the stimulatory NK cell receptor [52]. On the other hand, Tallerico et al reported that colorectal CSCs express higher levels of ligand for the natural cytotoxicity receptors that mediate NK-cell killing [53].…”

Section: Discussionmentioning

confidence: 99%

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

et al. 2016

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Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.

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Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

Cited by 167 publications

References 48 publications

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

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

Tumor-priming converts NK cells to memory-like NK cells

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

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