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Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells.

ABSTRACT: The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

SUBMITTER: Villalba M

PROVIDER: S-EPMC6970430 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells.

Villalba Martin M Alexia Catherine C Bellin-Robert Anais A Fayd'herbe de Maudave Alexis A Gitenay Delphine D

Frontiers in immunology 20200113

The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that n ...[more]

PMID: 31998309

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Project description:BACKGROUND:Previous evidence demonstrated that restoration of wild type VHL in human renal cancer cells decreased in vitro NK susceptibility. To investigate on the role of tumoral VHL status versus NK capability in renal cancer patients, 51 RCC patients were characterized for VHL mutational status and NK function. METHODS:VHL mutational status was determined by direct DNA sequencing on tumor tissue. NK cytotoxicity was measured against specific target cells K562, VHL-wild type (CAKI-1) and VHL-mutated (A498) human renal cancer cells through externalization of CD107a and IFN-? production. Activating NK receptors, NKp30, NKp44, NKp46, NKG2D, DNAM-1, NCAM-1 and Fc?RIIIa were evaluated through quantitative RT-PCR. RCC tumoral Tregs were characterized as CD4+CD25+CD127lowFoxp3+ and Treg function was evaluated as inhibition of T-effector proliferation. RESULTS:VHL mutations were detected in 26/55 (47%) RCC patients. IL-2 activated whole-blood samples (28 VHL-WT-RCC and 23 VHL-MUT-RCC) were evaluated for NK cytotoxicity toward human renal cancer cells A498, VHL-MUT and CAKI-1, VHL-WT. Efficient NK degranulation and increase in IFN-? production was detected when IL-2 activated whole-blood from VHL-MUT-RCC patients were tested toward A498 as compared to CAKI-1 cells (CD107a+NK: 7?±?2% vs 1?±?0.41%, p?=?0.015; IFN-?+NK: 6.26?±?3.4% vs 1.78?±?0.9% respectively). In addition, IL-2 activated NKs induced higher CD107a exposure in the presence of RCC autologous tumor cells or A498 as compared to SN12C (average CD107a+NK: 4.7 and 2.7% vs 0.3% respectively at 10E:1?T ratio). VHL-MUT-RCC tumors were NKp46+ cells infiltrated and expressed high NKp30 and NKp46 receptors as compared to VHL-WT-RCC tumors. A significant lower number of Tregs was detected in the tumor microenvironment of 13 VHL-MUT-RCC as compared to 13 VHL-WT-RCC tumors (1.84?±?0.36% vs 3.79?±?0.74% respectively, p?=?0.04). Tregs isolated from VHL-MUT-RCC patients were less suppressive of patients T effector proliferation compared to Tregs from VHL-WT-RCC patients (Teff proliferation: 6.7?±?3.9% vs 2.8?±?1.1%). CONCLUSIONS:VHL tumoral mutations improve NKs effectiveness in RCC patients and need to be considered in the evaluation of immune response. Moreover therapeutic strategies designed to target NK cells could be beneficial in VHL-mutated-RCCs alone or in association with immune checkpoints inhibitors.

Dataset Information

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells.

Publications

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells.

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