TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer

Maas, Ralph J. A.; Evert, Janneke S. Hoogstad-van; Meer, Jolien M R van der; Mekers, Vera E.; Rezaeifard, Somayeh; Korman, Alan J.; Jonge, Paul Kjd de; Cany, Jeannette; Woestenenk, Rob; Schaap, Nicolaas; Massuger, Leon F.A.G.; Jansen, Joop H.; Hobo, Willemijn; Dolstra, Harry

doi:10.1080/2162402x.2020.1843247

Cited by 54 publications

(72 citation statements)

References 54 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. We found that the circulating abundance of NK cells conveys positive prognostic value in individuals with M1 + 2 AML, but not among patients with M4 + 5 disease, correlating with markers of dysfunction that are aggravated in the M4 + 5 disease subtype ( Figure 1 ).…”

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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“…Importantly, the therapeutic effect of TIGIT antibody blockade was found to be NK cell-dependent as antibody-mediated NK cell depletion in mice 24 h prior to TIGIT blockade abrogated the positive effects of TIGIT antibody treatment [ 104 ]. Similar studies in human peripheral blood NK cells showed that TIGIT blockade enhanced their anti-tumor activity against soft-tissue sarcoma and ovarian carcinoma tumor targets in vitro, and significantly, reduced tumor burden of mice with ovarian carcinoma xenografts [ 105 , 106 ]. These encouraging pre-clinical results have led to the initiation of multiple clinical trials using monoclonal anti-TIGIT antibodies alone or in combination with other checkpoint inhibitors (NCT02913313, NCT04570839].…”

Section: Strategies To Overcome the Tumor Microenvironmentmentioning

confidence: 94%

Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

Navin

Lam

Parihar

2020

Cancers

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Natural killer (NK) cells are innate immune effectors capable of broad cytotoxicity via germline-encoded receptors and can have conferred cytotoxic potential via the addition of chimeric antigen receptors. Combined with their reduced risk of graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), NK cells are an attractive therapeutic platform. While significant progress has been made in treating hematological malignancies, challenges remain in using NK cell-based therapy to combat solid tumors due to their immunosuppressive tumor microenvironments (TMEs). The development of novel strategies enabling NK cells to resist the deleterious effects of the TME is critical to their therapeutic success against solid tumors. In this review, we discuss strategies that apply various genetic and non-genetic engineering approaches to enhance receptor-mediated NK cell cytotoxicity, improve NK cell resistance to TME effects, and enhance persistence in the TME. The successful design and application of these strategies will ultimately lead to more efficacious NK cell therapies to treat patients with solid tumors. This review outlines the mechanisms by which TME components suppress the anti-tumor activity of endogenous and adoptively transferred NK cells while also describing various approaches whose implementation in NK cells may lead to a more robust therapeutic platform against solid tumors.

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“…Spheroids can be derived from either established cell lines or primary isolated tumor cells [ 35 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ]. Usually, spheroids are obtained culturing tumor cells in ultra-low adherent plasticware or by hanging drop methods, forcing tumor cells to aggregate and generate tumor sphere in static or microfluidic systems [ 15 , 16 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 ].…”

Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning

confidence: 99%

“…The cross-talk between NK cells and solid tumor cells has also been assessed using spheroids of neuroblastoma, ovarian, cervical and breast carcinomas [ 121 , 123 , 163 , 164 , 165 ]. Neuroblastoma spheroids have been used to assess NK-cell mediated cytotoxicity upon treatment with nutlin-3a, a small molecule that antagonizes the inhibitory effect of MDM2 on p53.…”

Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning

confidence: 99%

“…The reactivation of p53 triggered the upregulation of DNAM1 ligands on neuroblastoma cells activating NK cell recognition and killing [ 165 ]. NK cells cultured with spheroids of ovarian cancer cells (IGROV1, SKOV3, OVCAR3) can downregulate the expression of DNAM1, the same happens co-culturing ovarian cancer specimens with NK cells [ 121 ]. The inhibitory effect mediated by DNAM1 downregulation was enforced by the upregulation of the inhibitory receptor TIGIT that can interact, like DNAM1, with PVR and nectin 2, while the levels of CD96, the third receptor for DNAM1 ligands, remained unaffected.…”

Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning

confidence: 99%

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Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

Poggi

Villa

Fernadez

et al. 2021

Cancers

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Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.

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TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer

Cited by 54 publications

References 54 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

Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

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