Calreticulin arms NK cells against leukemia

Fučíková, Jitka; Kline, Justin; Galluzzi, Lorenzo; Špíšek, Radek

doi:10.1080/2162402x.2019.1671763

Cited by 16 publications

(13 citation statements)

References 15 publications

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“…NK cells are key players of anti-AML immune responses 13 , 14 , 36 and express several co-inhibitory receptors that are commonly considered as prerogative of CTLs, including PD-1, 37 TIM-3 38 and TIGIT. 39 , 40 Inspired by our previous findings pointing to TIM-3 as the main co-inhibitory receptor that suppresses anticancer immunity in patients with ovarian carcinoma, 29 we therefore set to investigate the impact of TIM-3 on NK cell functions and disease progression in a prospectively collected cohort of 75 patients with AML.…”

Section: Discussionmentioning

confidence: 99%

TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

et al. 2021

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Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8 + cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyteassociated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML.

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Section: Discussionmentioning

confidence: 99%

TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

et al. 2021

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“…Drugs that induce ICD such as anthracyclines (doxorubicin, epirubicin, oxaliplatin and others) can trigger an effective antitumor immune response that suppresses tumor growth in mice because they make tumor cells immunogenic. This process involves the mobilization of calreticulin (CRT) to the tumor cell surface, the secretion and extracellular accumulation of ATP and several alarmins such as HMGB1 and annexin A1, and the production of type I IFN which, acting together, contribute to the inflammatory response that remodels the TME, suppress TAM and negatively affect tumor growth ( 290 – 293 , 295 , 337 – 339 ). ICD can also be induced by other immunomodulatory compounds such as agonists of RIG-I ( 340 , 341 ) or STING ( 288 , 342 ) because they promote the release or expression of several DAMP by tumor cells.…”

Section: Rational Design Of Combination Therapies That Target the Nkg2d-nkg2dl Axismentioning

confidence: 99%

Leveraging NKG2D Ligands in Immuno-Oncology

2021

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Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

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“…The antitumor response requires the participation of innate and adaptive immune cells. Innate immune cells include monocytes/macrophages, neutrophils, natural killer (NK) cells, NKT cells, γδT cells, eosinophils, basophils, and mast cells ( 45 , 46 ). DCs are professional antigen-presenting cells known to play a key role in the initiation and maintenance of antitumor immunity, bridging innate and adaptive immune responses ( 47 ).…”

Section: Innate Immune Cell-derived Evsmentioning

confidence: 99%

Immune Cell-Derived Extracellular Vesicles – New Strategies in Cancer Immunotherapy

et al. 2021

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Immune cell-derived extracellular vesicles (EVs) have increasingly become the focus of research due to their unique characteristics and bioinspired applications. They are lipid bilayer membrane nanosized vesicles harboring a range of immune cell-derived surface receptors and effector molecules from parental cells. Immune cell-derived EVs are important mediators of intercellular communication that regulate specific mechanisms of adaptive and innate immune responses. However, the mechanisms underlying the antitumor effects of EVs are still being explored. Importantly, immune cell-derived EVs have some unique features, including accessibility, storage, ability to pass through blood-brain and blood-tumor barriers, and loading of various effector molecules. Immune cell-derived EVs have been directly applied or engineered as potent antitumor vaccines or for the diagnosis of clinical diseases. More research applications involving genetic engineering, membrane engineering, and cargo delivery strategies have improved the treatment efficacy of EVs. Immune cell-derived EV-based therapies are expected to become a separate technique or to complement immunotherapy, radiotherapy, chemotherapy and other therapeutic modalities. This review aims to provide a comprehensive overview of the characteristics and functions of immune cell-derived EVs derived from adaptive (CD4+ T, CD8+ T and B cells) and innate immune cells (macrophages, NK cells, DCs, and neutrophils) and discuss emerging therapeutic opportunities and prospects in cancer treatment.

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Calreticulin arms NK cells against leukemia

Cited by 16 publications

References 15 publications

TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients

Leveraging NKG2D Ligands in Immuno-Oncology

Immune Cell-Derived Extracellular Vesicles – New Strategies in Cancer Immunotherapy

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