Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ

Schürch, Christian M.; Riether, Carsten; Amrein, Michael A.; Ochsenbein, Adrian F.

doi:10.1084/jem.20121229

Cited by 76 publications

(95 citation statements)

References 76 publications

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“…Reduced expression of MICA and MICB by BCSCs contributes to the resistance to NK cell cytotoxicity and the resultant metastasis Tumor-infiltrating immune cells release cytokines such as IFNg to regulate leukemic stem cells (8). However, we found that the expression of IFNg receptor a chain, an essential component of IFNg receptor for ligand binding and trafficking, was comparable between BCSCs and non-BCSCs (Supplementary Fig.…”

Section: Failure Of Tumor-infiltrating Nk Cells To Prevent the Metastmentioning

confidence: 84%

“…The potential for CSCs to avoid destruction by adaptive immunity has been documented in the context of CTL-mediated cytotoxicity (5-7, 9, 28). In addition, IFNg released by CTL promotes the proliferation of CSCs and contributes to leukemia progression (8). These observations demonstrate that tumor metastasis is associated with dynamic regulation of CSC evasiveness from adaptive immunity.…”

Section: Discussionmentioning

confidence: 97%

“…CSCs are the cellular origin of multiple malignant properties in cancer, including unrestrained self-renewal (2), neovascularization (3), resistance to chemo-or radiotherapy (2,27), dissemination (4), and evasion of antitumor immunity (5)(6)(7)(8)(9). The metastasis of BCSCs is a result of epithelial-to-mesenchymal transition (EMT) induced by genetic/epigenetic alterations or microenvironmental cues (4).…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells are highly heterogeneous and a small fraction of cancer cells with stem cell properties, known as tumor-initiating cells, or cancer stem cells (CSC), may be responsible for tumorigenesis (2), angiogenesis (3) and metastasis (4). Recently, selection by adaptive immunity has been shown to generate or enrich cancer cells with stemness (5)(6)(7)(8)(9), suggesting the presence of intimate interaction between CSCs and the skewed adaptive immunity in patients with cancer. However, the role of innate immunity in affecting CSCs and their metastasis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. Cancer Res; 74(20); 5746-57. Ó2014 AACR.

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Section: Failure Of Tumor-infiltrating Nk Cells To Prevent the Metastmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2014

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“…In analogy Moreover, in leukemia, BM-infiltrating immune cells may contribute to the LSC niche and especially activated T cells interact with and paradoxically support LSCs (12,13,44).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitor–induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling

et al. 2015

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In chronic myelogenous leukemia (CML), oncogenic BCR-ABL1 activates the Wnt pathway, which is fundamental for leukemia stem cell (LSC) maintenance. Tyrosine kinase inhibitor (TKI) treatment reduces Wnt-signaling in LSCs and often leads to molecular remission of CML; however, LSCs persist long-term despite BCR-ABL1 inhibition, ultimately leading to disease relapse. Here, we demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. CD70 triggered CD27-signaling and compensatory Wnt pathway activation. Consequently, combining TKIs with CD70 blockade effectively eliminated human CD34 + CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, TKI-induced expression of CD70 and compensatory Wnt-signaling via the CD70/CD27-interaction is a promising targetable resistance mechanism of CML LSCs.3

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From the niche to malignant hematopoiesis and back: reciprocal interactions between leukemia and the bone marrow microenvironment

et al. 2021

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The bone marrow microenvironment regulates hematopoiesis through a complex network of cellular and molecular components. Hematologic malignancies reside within, and extensively interact with, the same bone marrow microenvironment. These interactions consequently alter both malignant and benign hematopoiesis in multiple ways, and can encompass initiation of malignancy, support of malignant progression, resistance to chemotherapy, and loss of normal hematopoiesis. Herein, we will review supporting studies for interactions of the bone marrow microenvironment with hematologic malignancies and discuss challenges still facing this exciting field of research.This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

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Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ

Abstract: Cytotoxic T cells increase leukemia stem cell numbers in a murine model of chronic myeloid leukemia.

Cited by 76 publications

References 76 publications

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

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

Tyrosine kinase inhibitor–induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling

From the niche to malignant hematopoiesis and back: reciprocal interactions between leukemia and the bone marrow microenvironment

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