Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints

Shemesh, Avishai; Brusilovsky, Michael; Kundu, Kiran; Ottolenghi, Aner; Campbell, Kerry S.; Porgador, Angel

doi:10.1007/s00262-017-2104-x

Cited by 14 publications

(17 citation statements)

References 54 publications

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“…Such modulated NCR and KIR expression will affect their capacity to recognize and kill target tumor cells. Notably, splice variants of human NCR encoding receptor isoforms with inhibitory functions have been recently discovered, 39 influencing outcomes in many immunopathological contexts. 40 Such differential splicing arises in some tissue microenvironments where inhibitory NCR are triggered by specific ligands, as this is the case for the inhibitory isoform of NKp44 that cross-link Proliferating Cell Nuclear Antigen (PCNA) on tumor cells, a ligand expressed by many cancer types.…”

Section: Discussionmentioning

confidence: 99%

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

et al. 2019

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γδT cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion, their ability to kill tumor cells in an Human Leukocyte Antigen (HLA)-unrestricted manner, and their combination of features of both innate and adaptive immunity. These unique properties and functional plasticity render them very attractive both as targets and vectors for cancer immunotherapy. Yet, these potent and fascinating antitumor effectors have not been extensively explored in melanoma. We provided here a detailed investigation of the phenotypic and functional properties of circulating and tumor-infiltrating γδT cells in melanoma patients, and their impact on clinical evolution. High proportions of circulating-and tumor-infiltrating γδT and δ2+ subset were associated with better clinical outcome. We reported however that circulating and tumor-infiltrating γδT cells from melanoma patients displayed an altered expression of NCR, KIR, and immune checkpoints, and identified NKp44, PD1, 41BB/ 41BBL, TIM3, and LAG3 as crucial checkpoints allowing immune escape and tumor progression. Notably, melanoma drastically impaired the ability of γδT cells to exhibit activation molecules, secrete cytokines, and display cytotoxicity toward melanoma in response to stimulation with phosphoantigens. It drove them toward regulatory and Th17 profiles associated with poor clinical outcomes. Our study highlights that melanoma hijacked γδT cells to escape from immune control, and revealed that circulating and tumor-infiltrating γδT cell features are promising potential biomarkers of clinical evolution. Such understanding of the physiopathology of γδT cells may help designing new therapeutic approaches exploiting the antitumor potential of γδT cells while counteracting their skewing by tumors to improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

et al. 2019

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“…NKp46 and NKp30 are expressed on the cell membrane of human peripheral blood NK cells, most of them are CD56 dim NK cells, while NKp44 is expressed on IL-2-activated NK cells and CD56 bright NK cells [31]. And ligands are systemically summarized in Kruse study [32]. [36].…”

Section: Naturalmentioning

confidence: 99%

Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell

Yang

2020

Journal of Immunology Research

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NK cells are lymphocytes with antitumor properties and can directly lyse tumor cells in a non-MHC-restricted manner. However, the tumor microenvironment affects the immune function of NK cells, which leads to immune evasion. This may be related to the pathogenesis of some diseases. Therefore, great efforts have been made to improve the immunotherapy effect of natural killer cells. NK cells from different sources can meet different clinical needs, in order to minimize the inhibition of NK cells and maximize the response potential of NK cells, for example, modification of NK cells can increase the number of NK cells in tumor target area, change the direction of NK cells, and improve their targeting ability to malignant cells. Checkpoint blocking is also a promising strategy for NK cells to kill tumor cells. Combination therapy is another strategy for improving antitumor ability, especially in combination with oncolytic viruses and nanomaterials. In this paper, the mechanisms affecting the activity of NK cells were reviewed, and the therapeutic potential of different basic NK cell strategies in tumor therapy was focused on. The main strategies for improving the immune function of NK cells were described, and some new strategies were proposed.

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“…For example, the alternative isoform of NKp44 that lacks exon 5 (NKp44-1 △5 ) can inhibit NK cell activation, which is triggered by proliferating cell nuclear antigen (PCNA) (Table 1 ) [ 45 ]. PCNA is an inhibitory ligand of higher NKp44 expression found on the surface of tumor cells [ 46 ] and interacts with the NKp44-1 △5 isoform. Mechanically, in the presence of NKp44-1 △5 , PCNA in tumor cells is presented by human histocompatibility leukocyte antigen-1 (HLA-1) and is then recruited to the NK immunological synapses (NKIS), which, in turn, induce an inhibitory effect on NK cells [ 47 ].…”

Section: As and Tumor Innate Immune Responsesmentioning

confidence: 99%

The Roles of Alternative Splicing in Tumor-immune Cell Interactions

Wang

Zhang

Jiao

et al. 2020

CCDT

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: Alternative splicing (AS) plays a significant role in the hallmarks of cancer and can provide neoantigens for immunotherapy. Here, we summarize recent advances in immune system associated tumor specific-antigens (TSAs) produced by AS. We further discuss the regulating mechanisms involved in AS-mediated innate and adaptive immune responses and the anti-tumoral and pro-tumoral roles in different types of cancer. For example, ULBP1_RI, MLL5△21spe, NKp44-1△5, MHC-I△7, CD200S△1, 2, PVR α/β/γ/δ and IL-33 variants 1/2/3 act as regulators in solid tumors and IPAK4-L and, FOXP1ΔN100 exhibit functions in hematological cancers.

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Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints

Cited by 14 publications

References 54 publications

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell

The Roles of Alternative Splicing in Tumor-immune Cell Interactions

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