Unleashing the power of NK cells in anticancer immunotherapy

Vogler, Meike; Shanmugalingam, Senthan; Särchen, Vinzenz; Reindl, Lisa Marie; Grèze, Victoria; Buchinger, Leon; Kühn, Michael W.M.; Ullrich, Evelyn

doi:10.1007/s00109-021-02120-z

Cited by 18 publications

(12 citation statements)

References 111 publications

(126 reference statements)

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“…A large variety of new drugs able to enhance NK cell response are being tested in clinical trials, but a toxic effect has been reported for some of them ( 42 , 43 ). Development of small molecules targeting ERAP1 might provide an innovative tool to improve outcome of NK cell-based antitumor therapy protocols.…”

Section: Discussionmentioning

confidence: 99%

ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

et al. 2021

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The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

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Section: Discussionmentioning

confidence: 99%

ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

et al. 2021

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“…Based on high NK cell frequencies and high prevalence of tumor formation in the FRT, strategies for increasing tumor recognition by NK cells have been discussed. This includes the sensitizing of tumor cells for NK cell killing, improving the cytotoxicity of NK cells ex-vivo via cytokine treatment or the generation of tumor-specific NK cells generated via genetic engineering using chimeric antigen receptor (CAR)-expressing NK cells [ 75 , 76 ].…”

Section: Tissue-resident Immunity In the Endometriummentioning

confidence: 99%

Tissue-resident immunity in the female and male reproductive tract

2022

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The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and recirculate through secondary lymphoid organs. Instead, subsets of immune cells continuously reside in tissues until being reactivated, e.g., by a recurring pathogen or other stimuli. Consequently, the concept of tissue-resident immunity has emerged, and substantial evidence is now available to support its pivotal function in maintaining tissue homeostasis, sensing challenges and providing antimicrobial protection. Surprisingly, insights on tissue-resident immunity in the barrier tissues of the female reproductive tract are sparse and only slowly emerging. The need for protection from vaginal and amniotic infections, the uniqueness of periodic tissue shedding and renewal of the endometrial barrier tissue, and the demand for a tailored decidual immune adaptation during pregnancy highlight that tissue-resident immunity may play a crucial role in distinct compartments of the female reproductive tract. This review accentuates the characteristics of tissue-resident immune cells in the vagina, endometrium, and the decidua during pregnancy and discusses their functional role in modulating the risk for infertility, pregnancy complications, infections, or cancer. We here also review data published to date on tissue-resident immunity in the male reproductive organs, which is still a largely uncharted territory.

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“…Considering these immune evasion mechanisms, various strategies to enhance NK cell function have been developed (4,(37)(38)(39). Research into the optimal selection and dosing regimes of cytokines used for expansion and activation (39)(40)(41)(42) has identified IL-15 as the preferred choice (43), while work on membrane bound IL-15 and IL-21 has also shown advantages (44)(45)(46).…”

Section: Enhancing Nk Cell Functionmentioning

confidence: 99%

“…Despite engineered T cell therapies advancing through clinical trials to commercialization (1), some major challenges remain such as high rates of serious adverse side effects, production inefficiencies, and high costs for autologous treatment generation (2). Recent research has shown that NK cells can overcome these challenges to develop into an independent or complementary class of cancer immunotherapies (3)(4)(5)(6). A complementary field benefiting from advances in NK cell development is that of NK cell extracellular vesicles (NKEVs), with purified NKEVs having proven to reproduce key functions of their parent NK cells (7).…”

Section: Introductionmentioning

confidence: 99%

iPSCs in NK Cell Manufacturing and NKEV Development

Boyd-Gibbins¹,

Karagiannis

Hwang³

et al. 2022

Front. Immunol.

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Natural killer (NK) cell immunotherapies for cancer can complement existing T cell therapies while benefiting from advancements already made in the immunotherapy field. For NK cell manufacturing, induced pluripotent stem cells (iPSCs) offer advantages including eliminating donor variation and providing an ideal platform for genome engineering. At the same time, extracellular vesicles (EVs) have become a major research interest, and purified NK cell extracellular vesicles (NKEVs) have been shown to reproduce the key functions of their parent NK cells. NKEVs have the potential to be developed into a standalone therapeutic with reduced complexity and immunogenicity compared to cell therapies. This review explores the role iPSC technology can play in both NK cell manufacturing and NKEV development.

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Unleashing the power of NK cells in anticancer immunotherapy

Cited by 18 publications

References 111 publications

ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

Tissue-resident immunity in the female and male reproductive tract

iPSCs in NK Cell Manufacturing and NKEV Development

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