STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion

Hsu, Jung Mao; Xia, Weiya; Hsu, Yi Hsin; Chan, Li-Chuan; Yu, Wangsheng; Ho, Jin‐Nyoung; Chen, Chun‐Te; Liao, Hsin Wei; Kuo, Chu Wei; Khoo, Kay‐Hooi; Hsu, Jennifer L.; Li, Chia Wei; Lim, Seung Oe; Chang, Shannon; Chen, Yi Chun; Ren, Guo Xin; Hung, Mien‐Chie

doi:10.1038/s41467-018-04313-6

Cited by 325 publications

(289 citation statements)

References 62 publications

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“…BCSCs are resistant to chemotherapy and radiation [2,6,41,43] and recent studies demonstrated that BCSCs escape from innate and adaptive immune responses, which suggests that BCSCs are resistant to immunotherapy as well [44][45][46][47][48]. These findings underscore the importance of developing novel approaches that make BCSCs as sensitive as non-BCSCs to conventional therapies and immunotherapy in order to develop successful and curative treatments for breast cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Sun

Yang

Toprani³

et al. 2020

Cell Commun Signal

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Background: The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response. Methods: High aldehyde dehydrogenase activity (ALDH) bright and CD44 + /CD24 − /ESA + cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA). Results: We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors. Conclusion: DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Sun

Yang

Toprani³

et al. 2020

Cell Commun Signal

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“…Another interesting finding regsrding CSC maintenance is that programmed death ligand 1 (PD-L1, also known as CD274) could stimulate CSC expansion via the high mobility group A (HMGA)-dependent Akt and ERK pathways [140]. PD-L1 in CSCs also confers immune evasion, thereby sustaining the tumorigenesis of CSCs [141]. Recently, miR-873-5p was shown to target PD-L1, thus attenuating breast cancer stemness [142] (Table 4).…”

Section: Mirnas Regulating Nf-κb Signaling and Pd-l1mentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

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“…Over the last two decades, human tumor cells with stem cell properties (stemness) have been identified and demonstrated to initiate tumorigenesis and accelerate progression, coupled with therapy resistance, immune evasion and distant metastases [5][6][7][8][9][10][11][12] . However, targeting cancer stemness has yet to be widely achieved in the cancer clinic and therefore demands a better understanding and identification of targetable stemness regulators.…”

Section: Introductionmentioning

confidence: 99%

ITGA2is a target of miR-206 promoting cancer stemness and lung metastasis through enhancedACLYandCCND1expression in triple negative breast cancer

Adorno-Cruz

Hoffmann²,

Liu

et al. 2019

Preprint

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AbstractAccumulating evidence demonstrates that cancer stemness is essential for both tumor development and progression, regulated by multi-layer factors at genetic, epigenetic and micro-environmental levels. However, how to target stemness-driven plasticity and eliminate metastasis remains one of the biggest challenges in the clinic. We aim to identify novel molecular mechanisms underlying stemness of triple negative breast cancer (TNBC) which frequently metastasizes to the visceral organs but lacks targeted therapies. Following our previous discovery of miR-206 as an epigenetic suppressor of tumorigenesis and metastasis, we now report that the integrin receptor CD49b-encodingITGA2is an oncogenic target of miR-206 in TNBC.ITGA2knockdown abolished cancer stemness (mammosphere formation, pluripotency marker expression, and FAK phosphorylation), inhibited cell cycling, compromised migration and invasion, and thereby decreasing lung metastasis of TNBC. RNA sequencing analyses of breast cancer cells revealed thatITGA2knockdown inhibits gene expression essential for both classical integrin-regulated pathways (cell cycle, wounding response, protein kinase, etc) and newly identified pathways such as lipid metabolism. Notably,ACLY-encoded ATP citrate lyase is one of the top targets in CD49b-regulated lipid metabolism andCCND1-encoded Cyclin D1 represents regulation of cell cycle and many other pathways. ACLY, known to catalyze the formation of cytosolic acetyl-CoA for fatty acid biosynthesis, is indispensable for cancer stemness. Overexpression ofCCND1rescues the phenotype ofITGA2knockdown-induced cell cycle arrest. High expression levels of theITGA2/ACLY/CCND1axis are correlated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifiesITGA2as a potential therapeutic target of TNBC stemness and metastasis.

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STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion

Cited by 325 publications

References 62 publications

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

ITGA2is a target of miR-206 promoting cancer stemness and lung metastasis through enhancedACLYandCCND1expression in triple negative breast cancer

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