IntechOpen

Home > Books > Advances in Cancer Immunotherapy [Working Title]

Open access peer-reviewed chapter - ONLINE FIRST

Challenges and Recent Advances in NK-Mediated Adoptive Cell Therapies against Cancer

Written By

Tianxiang Zhang

Submitted: 12 December 2023 Reviewed: 18 December 2023 Published: 06 May 2024

DOI: 10.5772/intechopen.1004181

Advances in Cancer Immunotherapy IntechOpen
Advances in Cancer Immunotherapy Edited by Shin Mukai

From the Edited Volume

Advances in Cancer Immunotherapy [Working Title]

Dr. Shin Mukai

Chapter metrics overview

8 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Natural killer (NK) cells play a crucial role in the innate immune system. Unlike adaptive immune cells that rely on specific antigen receptors, NK cell activity is governed by germline-encoded activating or inhibitory receptors expressed on the cell surface. The integration of signals from these receptors determines the NK cell response. Activated NK cells demonstrate potent cytotoxicity against target cells. The distinctive attributes of NK cells, marked by quick response, robust cytotoxicity, and the absence of antigen receptors, position them as promising tools in cancer immunotherapy. Ongoing clinical trials are actively assessing NK cells and related reagents, showing promising outcomes. However, significant challenges arise from the immunosuppressive mechanisms within the tumor microenvironment, impeding the broader application of NK cells. In-depth studies on these mechanisms are imperative to identify solutions, ultimately paving the way for the widespread clinical utilization of NK cells in cancer immunotherapy.

Keywords

  • nature killer cells
  • chimera antigen receptor
  • adoptive cell therapy
  • tumor immunology
  • immunotherapy
  • tumor microenvironment
  • ADCC

1. Introduction

Natural killer (NK) cells were first described in the 1970s [1, 2, 3]. They belong to the innate immune system [4]. More recent studies categorize NK cells as a member of the innate lymphocyte cell (ILC) family [5]. The major site for NK cell development is bone marrow, where NK cells share the same progenitor cells as adaptive immune cells, including both T and B cells [6]. Different from these adaptive immune cells, NK cells do not express antigen receptors but a series of activation or inhibitory receptors that can be triggered by their ligands, usually upregulated or released by viral infected or transformed cells [7, 8, 9]. This recognition is quick and, once activated, NK cells can induce apoptosis of target cells without presensitization [1, 2, 3]. There are several well-studied activating or inhibitory receptors and pathways governing NK cell activity [7, 8, 9]. Among them, the killer Ig-like receptor (KIR) and human leukocyte antigens (HLA) class I axis, or the Ly49 family and major histocompatibility complex (MHC) class I axis in mice, are considered to be the major pathway that is involved in NK cell education, mediate the “missing-self” reaction, and inhibit NK cells’ activation in normal tissues [9]. The final response of NK cells relies on the integrated signals delivered by all activation and inhibitory signals [9].

During the past several years, adoptive cell therapy (ACT) based cancer immunotherapy has achieved huge success in treating hematopoietic cancers [10]. As a group of robust effector cells, NK has been drawing more and more attention. Compared with T cells, NK cells do not express T-cell receptors and will not induce graft-versus-host disease (GVHD) when applied allogenically [8, 10]. Meanwhile, NK cells can mount a rapid response against target cells in both in vitro and in vivo studies [1, 2, 3]. Indeed, the allogenic application of NK cells was approved to be safe, and the tumor-controlling capability was promising in adult myeloid leukemia patients [11, 12]. Nevertheless, immune suppressive factors, especially in the microenvironment of solid tumors, dampen the efficacy of NK cells, highlighting the importance of deeper mechanism studies [10, 13]. In this chapter, we will review some basic biology of NK cells and how NK cells were applied for cancer treatment, with a focus on the challenges and advances in NK-mediated ACT.

Advertisement

2. The general biology of NK cells

Mature murine NK cells are characterized by signature markers NK1.1+, Nkp46+, and Ly49+, while human NK cells are typically identified as CD3-CD56+ [6]. Unlike adaptive immune cells, NK cells can mature into effector cells independently of the thymus, recombination-activating genes, or activation-induced cytidine deaminase activity [6]. This independence means NK cells lack antigen receptors encoded by rearranged genes, such as the T-cell antigen receptor (TCR) and immunoglobulins [6, 14]. Despite this, NK cells can effectively respond to viral infections or cellular transformation, showcasing various effector functions, notably cytotoxicity and the production of pro-inflammatory cytokines [1, 2, 3, 14]. Importantly, NK cell activation does not necessitate prior sensitization, positioning them as sentinel cells integral to immune surveillance [4].

NK cells express a series of activating and inhibitory receptors on the cell surface [9]. The outcome of NK cell activity depends on the result of integrating all the signals received by these receptors (Figure 1) [9]. NK cells exhibit versatile mechanisms in targeting cells, particularly at inflammatory sites guided by chemokine gradients produced by innate or adaptive immune cells [15, 16]. Predominant chemokine-chemokine receptor pathways facilitating NK recruitment include CXCR3–CXCR4, CX3CR1, and CCR3–CCR5 [17]. Upon reaching inflammatory sites, NK cells employ the “missing-self” mechanism, where KIR molecules recognize decreased MHC class I expression on tumor or virally infected cells, relieving inhibitory signals and leading to target cell lysis [9]. Simultaneously, upregulated ligands on these cells bind activating receptors (e.g., NCRs) on NK cell surfaces, initiating natural killing [9]. This unique feature positions NK cells as potential candidates for treating malignancies, evading T-cell recognition and restriction [18].

Figure 1.

Activating and inhibitory receptors expressed by human NK cells. Some activating and inhibitory receptors expressed by human NK cells are illustrated. KIR2DL1 and KIR3DL1 were used to represent all KIR2D and KIR3D subfamily members.

Another pivotal mechanism in target cell elimination is antibody-dependent cell-mediated cytotoxicity (ADCC). CD16 on NK cell surfaces recognizes the Fc part of antibodies binding to target cells, triggering strong activating signals, degranulation, and target cell lysis [9]. Emerging evidence underscores the significance of ADCC in the clinical success of therapeutic antibodies like rituximab and trastuzumab [19, 20].

Both natural killer activity and ADCC culminate in the release of granzymes and perforin, along with the expression of death ligands such as fas cell surface death receptor ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), inducing cell death [14]. Additionally, NK cells release cytokines, including IFN-γ and TNF-α, contributing to the sustained restriction of target cells [14]. This multifaceted approach highlights the potency of NK cells in combating various cellular threats and underscores their therapeutic potential in addressing malignancies with diverse immune escape strategies.

Advertisement

3. NK-based ACT

In 2013, the cancer-immunity cycle model was introduced as a conceptual framework outlining the functioning of the immune system in regulating tumors [21]. Building on this, the NK cell-cancer cycle model was subsequently proposed, delineating how NK cells exert control over tumor growth (Figure 2) [13]. This model delineates several pivotal steps in the process, encompassing the infiltration of NK cells into the tumor lesion, the recognition, and activation of NK cells in response to tumors, the subsequent elimination of tumor cells, and the orchestration of the tumor immune microenvironment [13]. This model offers a comprehensive view of the dynamic interplay between NK cells and cancer, providing insights into the sequential events crucial for NK cells to effectively counteract and manage tumor progression.

Figure 2.

NK cancer cycle and research priorities dedicated to promoting NK-based immunotherapy (modified from Bald et al. [13]). Once NK cells are recruited to the local tumor lesion, they recognize tumor cells through a series of receptor-ligand interactions. After activation, NK cells kill tumor cells; meanwhile, they release cytokines and chemokines to orchestrate the adaptive immune system and recruit more immune cells to the tumor site. Current research focuses on several aspects, including augmenting infiltration, enhancing recognition and specificity, fortifying NK cells’ fitness through cytokines, blocking immune checkpoints, and overcoming the immunosuppressive tumor microenvironment (TME).

The infiltration of NK cells into tumor lesions is a pivotal step in restraining tumor growth, and numerous studies have demonstrated a positive correlation between the abundance and persistence of NK cells in the tumor microenvironment (TME) and increased overall patient survival [22, 23, 24, 25, 26, 27, 28, 29]. Chemokines and their corresponding receptors play a crucial role in recruiting NK cells, with CD56dim and CD56bright NK cells in human peripheral blood exhibiting distinct chemokine receptor expression profiles [30]. CD56bright NK cells typically express CCR2, CCR5, CCR7, CXCR3, CXCR4, and CD62L, while CD56dim NK cells express CXCR1, CXCR2, CXCR4, CX3CR1, S1P5, and ChemR23 [10].

Upon entering the TME, NK cells make critical decisions based on the integration of both activating and inhibitory signals. Human NK cells express killer cell immunoglobulin-like receptors (KIRs) that inhibit their activity upon binding to HLA class I molecules expressed on other cells, a mechanism crucial for self-recognition [9]. Tumor cells, under the adaptive immune system’s pressure, often downregulate HLA-I expression, releasing inhibition and lowering the threshold for NK cell activation [31].

Tumor-infiltrating NK cells express activating receptors, including CD16, natural cytotoxicity receptors (NCRs), and NKG2D, which respond to ligands within the TME [7, 8, 9, 14, 32]. When activating signals surpass inhibitory ones, NK cells employ multiple mechanisms to secrete effector molecules, inducing tumor cell apoptosis [33, 34]. Activated NK cells also produce pro-inflammatory cytokines, including IFN-γ, GM-CSF, G-CSF, M-CSF, TNF, IL-5, IL-10, and IL-13, reshaping the immune landscape of tumors [14].

Among these cytokines, IFN-γ is one of the best-studied cytokines and plays a multifaceted role in the context of antitumor immune responses [35]. It upregulates the expression of MHC class II and co-stimulatory molecules on antigen-presenting cells and enhances the antigen-processing machinery [36]. It also promotes the nonspecific cytocidal activity of macrophages toward tumors [37]. IFN-γ also affects T cells directly. Signaling through IFN-γ in CD4+ T cells can prompt the development of an antitumor TH1 phenotype [38]. This, in turn, leads to an upregulation of granzyme and IL-2 receptor expression on CD8+ T cells, empowering these cells to achieve their maximum cytotoxic potential [35, 39]. IFN-γ stimulates dendritic cells to produce cytokines IL-12 and IL-15 [40]. Together with IFN-γ, these cytokines strongly induce antitumor responses by CD4+ Th1 and cytotoxic CD8+ T cells [41, 42, 43]. IFN-γ also augments MHC-I expression on tumor cells, increasing their immunogenicity and susceptibility to recognition by adaptive immune cells [40].

Advertisement

4. Challenges and advances

4.1 Enhance recognition and specificity

The activation of NK cells within tumor lesions is often inadequate due to the heterogeneous and suppressive features of the tumor microenvironment (TME) [10, 13]. Many tumor cells lack sufficient expression of ligands capable of overriding the inhibitory signals delivered by the same cell [44]. Furthermore, in contrast to adaptive immune cells, NK cells do not possess antigen-specific receptors [9]. Consequently, enhancing tumor specificity and improving killing efficacy represent crucial areas garnering considerable research efforts [7, 10, 13, 14].

Chimeric antigen receptors (CARs) are synthetic fusion proteins that combine an extracellular antigen-recognition domain with intracellular signaling moieties to activate cells [10]. Initially tested on T cells, this unique structure delivers potent antigen-specific activation signals to CAR-bearing T cells, leading to substantial clinical success in chimeric antigen receptor T cells (CAR-T) cell therapy [45, 46, 47, 48, 49, 50, 51]. Notably, CARs have been successfully adapted for use in generating CAR-NK cells [52, 53]. Clinical trials with a CD19-specific CAR-NK therapy have demonstrated success [54]. Recently, interest has shifted toward designing CARs based on activating signals associated with NK cell biology [55, 56, 57]. This includes utilizing adapter proteins like DNAX-activation protein 12 (DAP12) and DAP10 in place of CD3ζ, which has shown efficacy in targeting tumors [57, 58, 59].

One critical challenge encountered in the clinical application of CART cell therapy is antigen loss, a phenomenon that contributes to immune evasion by cancer cells [60]. To tackle this challenge, ongoing efforts focus on refining CAR strategies. One approach involves redesigning CARs to target multiple antigens or engage multiple pathways simultaneously [61, 62, 63]. The use of dual-CAR or bi-specific CAR designs entails the expression of two different CARs, with each binding to a specific antigen, or incorporating two distinct antigen-recognition domains within a single CAR [61, 62, 63]. These designs provide greater flexibility in customization, allowing each CAR to be formatted with both antigen specificity and co-stimulatory signals [61, 62, 63].

Enhancing control over CAR-mediated activation is essential to minimize toxicities arising from off-tumor effects [64]. Logic-gated CARs, initially demonstrated in CAR T cells, hold promise for regulating CAR-NK activity [65, 66, 67, 68, 69]. Preliminary findings indicate the potential to control CAR-NK activity using logic-gated CAR gene circuits [65, 66, 67, 68, 69]. This approach aims to target specific antigens on tumor cells while avoiding interactions with healthy cells [70, 71, 72].

Despite the success of CAR-based approaches in targeting surface proteins, a limitation is their inability to detect intracellular antigens [73]. An innovative strategy involves engineering NK cells to express a T-cell receptor (TCR), enabling the recognition of intracellular antigens presented as peptide-HLA complexes [74]. TCR-guided NK-92 cells have demonstrated success in mediating antitumor responses, presenting a potential advantage in avoiding mispairing issues observed in TCR-engineered T cells [74].

NK cell engagers are novel designs that trigger activating receptors on NK cells while binding target antigens on tumor cells [75, 76, 77, 78, 79]. Tri-specific and tetra-specific engagers aim to enhance the antitumor effect by targeting multiple antigens or linking cytokines to support NK cell expansion [80, 81, 82, 83]. Unlike engineered approaches, engagers bypass gene transfer, offering a simpler and more cost-effective manufacturing process with CAR-like activity [84]. Preclinical studies show promising results in targeting hematologic and solid malignancies [85, 86]. Tri-specific molecules targeting CLEC12A and activating NK cells through engaging CD16 and IL-15 receptors demonstrated a robust response against primary acute myeloid leukemia (AML) blasts [83]. Trifunctional engagers targeting CD16 and NKp46 efficiently controlled tumor growth in solid and metastatic malignancies [87]. Cord blood NK cells complexed with AFM13, a bi-specific engager, exhibited enhanced killing of CD30+ tumor cells, translating to clinical trials for relapsed/refractory CD30+ lymphomas [79]. As strategies advance to clinical trials, assessing the durability of engager-loaded NK cells’ antitumor effect and determining the need for multiple treatments become crucial considerations [8].

4.2 Strengthen NK cells’ fitness by cytokines

Efforts to enhance NK cell function encompass not only genetic redirection through CAR and TCR engineering but also strategies to prime NK cells ex vivo and in vivo for sustained antitumor efficacy [88]. The cytolytic capacity of freshly isolated NK cells can be further enhanced by cytokine-mediated activation [89]. Ex vivo expansion with IL-2, IL-15, and IL-21 has shown promise in enhancing cytotoxic function, supporting proliferation, and maintaining a nonexhausted state [89]. Another approach involves exposing NK cells to IL-12/15/18, inducing a cytokine-induced memory-like NK cell phenotype that has demonstrated clinical efficacy in patients with relapsed myeloid neoplasias [90, 91]. Additionally, memory-like NK cells engineered with CARs exhibit increased potency against NK-resistant malignancies [92, 93], as observed in clinical trials targeting CD30+ lymphomas with NK cell engagers like AFM13 [79].

While cytokine priming offers advantages, prolonged ex vivo stimulation can render NK cells “cytokine-addicted,” resulting in decreased persistence without in vivo cytokine support [89]. To overcome this challenge, genetic engineering is employed to modify NK cells for autocrine cytokine production, ensuring sustained potency, proliferation, and persistence. CAR-engineered NK cells equipped with additional cytokine signaling, whether released into the environment or in membrane-bound form, exhibit superior persistence in preclinical models [54, 94]. Notably, IL-15-armored CAR-NK cells demonstrated prolonged circulation in patients with CD19+ lymphoid malignancies a year after treatment [54, 94]. These cytokines function not only in a cis manner to enhance NK cells’ function but also in a trans manner, inducing a bystander effect that activates other immune effector cells in the tumor microenvironment, potentially amplifying the antitumor response [54, 94]. Optimizing cytokine dosing strategies is crucial for supporting increased function and persistence without inducing metabolic exhaustion [10, 95, 96]. These multifaceted approaches, combining genetic engineering with cytokine modulation, signify a comprehensive strategy to enhance NK cell-based immunotherapies and overcome limitations associated with ex vivo stimulation [54, 94, 95, 96].

4.3 Blocking immune checkpoints

Tumors employ intricate mechanisms, including immune checkpoint engagement, to evade immune surveillance, potentially restraining NK cells similarly to T cells [10]. Efforts to replicate the clinical success of T-cell checkpoint blockade, such as targeting PD1 and CTLA4, have explored modulating these regulatory circuits in NK cells [97, 98, 99, 100, 101, 102]. While some studies suggest their role as functional suppressors, their overall relevance in NK cell biology remains debated [103, 104]. Other regulators like TIM3 [105], TIGIT [106, 107, 108], and LAG3 [109] have been investigated, and monoclonal antibody targeting has shown promise in reversing tumor-induced NK dysfunction in vitro.

Inhibitory killer cell immunoglobulin-like receptors (KIRs) are potent negative regulators overriding activating signals, attracting interest for their role in suppressing NK cell function. Lirilumab, an anti-panKIR2D antibody, aims to activate NK cells by blocking inhibitory KIRs [110]. However, clinical trials yielded limited success, possibly due to the crucial role of inhibitory KIRs in NK cell education [111, 112]. CD94/NKG2A is another significant NK cell regulator, and monalizumab, disrupting the NKG2A-HLA-E interaction, showed promise in treating recurrent or metastatic squamous cell carcinoma of the head and neck [113].

The current checkpoint-blocking approaches often rely on monoclonal antibodies, requiring multiple infusions due to their limited half-life [114]. Genetic editing advancements allow stable modification of NK cells to regulate mechanisms enhancing effector function [115, 116, 117]. For example, disrupting inhibitory receptor NKG2A genetically demonstrated superior tumor control in mouse models [116]. Moreover, genetic engineering targeting CIS (cytokine-inducible SH2-containing protein), a negative regulator of NK cell function, resulted in CAR-NK cells with enhanced metabolic fitness and increased antitumor activity [115, 117].

These studies mentioned above highlight the potential of targeted genetic perturbations to modulate NK cell biology. Moving forward, unbiased high-throughput discovery approaches are expected to systematically elucidate the functional consequences of specific genetic interventions, informing the design of the next generation of NK cell immunotherapies. The convergence of genetic editing capabilities and in-depth functional understanding offers exciting prospects for advancing NK cell-based immunotherapies.

4.4 Overcome immune suppressive TME

The TME presents a challenging metabolic landscape with immunosuppressive features, including glucose and amino acid deprivation, hypoxia, acidity, and an influx of suppressor cells like myeloid-derived suppressor cells (MDSCs) and Tregs [107, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135]. In solid tumors, hypoxia is a significant driver of immune cell dysfunction, impairing NK cell function directly and through the presence of immunosuppressive cells [107, 119, 121, 122]. Inhibiting hypoxia-responsive HIF1a signaling in NK cells has been shown to enhance their potency and unleash antitumor function [118].

Tumors exhibit aberrant metabolic behaviors, including high lactic acid levels, nutrient depletion, and increased concentrations of catabolites, adenosine, and reactive oxygen species [120, 128]. To overcome metabolic immunosuppression, current strategies focus on altering tumor metabolism or modifying gene expression in immune cells. Glycolytic inhibitors and lactate dehydrogenase (LDH) blockers show promise, with studies demonstrating improved T-cell antitumor cytotoxicity [124]. Targeting lactate transporters, MCT1 and MCT4, is also under investigation in clinical trials [125]. Adenosine, a by-product of adenosine triphosphate (ATP) metabolism, negatively regulates T-cell and NK cell function in the TME [123, 126, 127, 131]. Strategies to overcome adenosine-mediated immunosuppression include blocking CD73 on tumor cells and genetic editing to delete the adenosine A2A receptor in CAR T cells and CAR-NK cells, showing promise in preclinical studies [129, 134, 136]. Transforming growth factor-beta (TGFβ) signaling is another immunosuppressive mechanism in the TME, adversely affecting NK cell function [133]. Targeted deletion of the TGFβ receptor in NK cells and rendering CB-NK cells immune to TGFβ signaling have demonstrated improved NK cytotoxicity [130, 132, 135].

Given modulating immunometabolism in the TME is a promising direction, striking a balance in modulating immunometabolism is essential, considering that some metabolites are crucial for normal metabolism. Ongoing developments suggest a combined approach involving TME modulation and NK cell engineering could reduce immunosuppression, fostering robust immune cell activity. As these strategies advance, achieving a physiologic balance will be key to optimizing their effectiveness in cancer immunotherapy.

Advertisement

5. Concluding remarks

NK cells have demonstrated significant therapeutic potential in the treatment of AML patients, not only in an autologous context but also through the ex vivo differentiation and expansion of NK cells from various sources for allogeneic application. The transfusion of allogeneic NK cells has shown remarkable safety and antitumor efficacy. However, there is still ample room for improvement in overall efficacy, particularly in the treatment of solid tumors. Current research and advancements are concentrated on several facets of the interaction between NK cells and tumor cells. These include, but are not limited to, augmenting infiltration, enhancing recognition and specificity, fortifying NK cells’ fitness through cytokines, blocking immune checkpoints, and overcoming the immunosuppressive tumor microenvironment (TME). Genetic modifications have been employed to equip NK cells with chemokines, cytokines, CARs, or TCRs. Multi-specific NK cell engagers are also undergoing active clinical testing. All these approaches are designed to surmount the immunosuppressive challenges posed by the tumor microenvironment and enhance the efficacy of NK-mediated immunotherapies.

In recent times, concerns about safety have arisen in connection with malignancies associated with the genetic manipulation of transferred immune cells [137]. While ongoing discussions primarily center around CAR T cells, it is anticipated that genetically modified NK cells will encounter similar challenges. The use of virus-free methods for gene delivery may mitigate these risks. Furthermore, the in vivo editing of lymphocytes and other cells through the application of lipid nanoparticles represents a cutting-edge development in the field of cell and gene therapy [138, 139]. As these technologies progress, new avenues of research are continually unfolding.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Kiessling R, Klein E, Wigzell H. "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. European Journal of Immunology. 1975;5(2):112-117
  2. 2. Kiessling R, Klein E, Pross H, Wigzell H. "Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. European Journal of Immunology. 1975;5(2):117-121
  3. 3. Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. International Journal of Cancer. 1975;16(2):230-239
  4. 4. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331(6013):44-49
  5. 5. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: Regulators and effectors of immunity and tissue remodeling. Nature Immunology. 2011;12(1):21-27
  6. 6. Colucci F, Caligiuri MA, Di Santo JP. What does it take to make a natural killer? Nature Reviews. Immunology. 2003;3(5):413-425
  7. 7. Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nature Reviews. Immunology. 2023;23(2):90-105
  8. 8. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nature Reviews. Clinical Oncology. 2021;18(2):85-100
  9. 9. Lanier LL. NK cell recognition. Annual Review of Immunology. 2005;23:225-274
  10. 10. Laskowski TJ, Biederstadt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nature Reviews. Cancer. 2022;22(10):557-575
  11. 11. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051-3057
  12. 12. Curti A, Ruggeri L, Parisi S, Bontadini A, Dan E, Motta MR, et al. Larger size of donor alloreactive NK cell repertoire correlates with better response to NK cell immunotherapy in elderly acute myeloid leukemia patients. Clinical Cancer Research. 2016;22(8):1914-1921
  13. 13. Bald T, Krummel MF, Smyth MJ, Barry KC. The NK cell-cancer cycle: Advances and new challenges in NK cell-based immunotherapies. Nature Immunology. 2020;21(8):835-847
  14. 14. Miller JS, Lanier LL. Natural killer cells in cancer immunotherapy. Annual Review of Cancer Biology. 2019;3(1):77-103
  15. 15. Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B. Activation of NK cells by CC chemokines. Chemotaxis, Ca2+ mobilization, and enzyme release. Journal of Immunology. 1996;156(1):322-327
  16. 16. Maghazachi AA, al-Aoukaty A, Schall TJ. C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells. Role for G proteins. Journal of Immunology. 1994;153(11):4969-4977
  17. 17. Bernardini G, Antonangeli F, Bonanni V, Santoni A. Dysregulation of chemokine/chemokine receptor axes and NK cell tissue localization during diseases. Frontiers in Immunology. 2016;7:402
  18. 18. Malmberg KJ, Sohlberg E, Goodridge JP, Ljunggren HG. Immune selection during tumor checkpoint inhibition therapy paves way for NK-cell "missing self" recognition. Immunogenetics. 2017;69(8-9):547-556
  19. 19. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. Journal of Clinical Oncology. 2003;21(21):3940-3947
  20. 20. Varchetta S, Gibelli N, Oliviero B, Nardini E, Gennari R, Gatti G, et al. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Research. 2007;67(24):11991-11999
  21. 21. Chen DS, Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity. 2013;39(1):1-10
  22. 22. Wu M, Mei F, Liu W, Jiang J. Comprehensive characterization of tumor infiltrating natural killer cells and clinical significance in hepatocellular carcinoma based on gene expression profiles. Biomedicine & Pharmacotherapy. 2020;121:109637
  23. 23. Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nature Medicine. 2018;24(8):1178-1191
  24. 24. Bottcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell. 2018;172(5):1022-1037.e14
  25. 25. Takanami I, Takeuchi K, Giga M. The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma. The Journal of Thoracic and Cardiovascular Surgery. 2001;121(6):1058-1063
  26. 26. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 2000;88(3):577-583
  27. 27. Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, et al. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer. 2002;35(1):23-28
  28. 28. Muntasell A, Rojo F, Servitja S, Rubio-Perez C, Cabo M, Tamborero D, et al. NK cell infiltrates and HLA class I expression in primary HER2(+) breast cancer predict and uncouple pathological response and disease-free survival. Clinical Cancer Research. 2019;25(5):1535-1545
  29. 29. Remark R, Alifano M, Cremer I, Lupo A, Dieu-Nosjean MC, Riquet M, et al. Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: Influence of tumor origin. Clinical Cancer Research. 2013;19(15):4079-4091
  30. 30. Melsen JE, Lugthart G, Lankester AC, Schilham MW. Human circulating and tissue-resident CD56(bright) natural killer cell populations. Frontiers in Immunology. 2016;7:262
  31. 31. Hicklin DJ, Marincola FM, Ferrone S. HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Molecular Medicine Today. 1999;5(4):178-186
  32. 32. Reina-Ortiz C, Giraldos D, Azaceta G, Palomera L, Marzo I, Naval J, et al. Harnessing the potential of NK cell-based immunotherapies against multiple myeloma. Cells. 2022;11(3):392
  33. 33. Browne KA, Blink E, Sutton VR, Froelich CJ, Jans DA, Trapani JA. Cytosolic delivery of granzyme B by bacterial toxins: Evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Molecular and Cellular Biology. 1999;19(12):8604-8615
  34. 34. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of NK cell cytotoxicity. Molecular Immunology. 2005;42(4):501-510
  35. 35. Alspach E, Lussier DM, Schreiber RD. Interferon gamma and its important roles in promoting and inhibiting spontaneous and therapeutic cancer immunity. Cold Spring Harbor Perspectives in Biology. 2019;11(3):a028480
  36. 36. Pan J, Zhang M, Wang J, Wang Q , Xia D, Sun W, et al. Interferon-gamma is an autocrine mediator for dendritic cell maturation. Immunology Letters. 2004;94(1-2):141-151
  37. 37. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. Journal of Cellular Physiology. 2018;233(9):6425-6440
  38. 38. Bradley LM, Dalton DK, Croft M. A direct role for IFN-gamma in regulation of Th1 cell development. Journal of Immunology. 1996;157(4):1350-1358
  39. 39. Burke JD, Young HA. IFN-gamma: A cytokine at the right time, is in the right place. Seminars in Immunology. 2019;43:101280
  40. 40. Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-gamma in tumor progression and regression: A review. Biomarker Research. 2020;8:49
  41. 41. Kelly JM, Darcy PK, Markby JL, Godfrey DI, Takeda K, Yagita H, et al. Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nature Immunology. 2002;3(1):83-90
  42. 42. Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(20):11521-11526
  43. 43. Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H, Reusch U, et al. Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity. 2003;19(4):561-569
  44. 44. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK-cell function. European Journal of Immunology. 2014;44(6):1582-1592
  45. 45. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. The New England Journal of Medicine. 2018;378(5):439-448
  46. 46. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. The New England Journal of Medicine. 2019;380(1):45-56
  47. 47. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. The New England Journal of Medicine. 2017;377(26):2531-2544
  48. 48. Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. The New England Journal of Medicine. 2018;378(5):449-459
  49. 49. Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. The New England Journal of Medicine. 2020;382(14):1331-1342
  50. 50. Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. The New England Journal of Medicine. 2021;384(8):705-716
  51. 51. Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. The New England Journal of Medicine. 2019;380(18):1726-1737
  52. 52. Biederstadt A, Rezvani K. Engineering the next generation of CAR-NK immunotherapies. International Journal of Hematology. 2021;114(5):554-571
  53. 53. Daher M, Rezvani K. Outlook for new CAR-based therapies with a focus on CAR NK cells: What lies beyond CAR-engineered T cells in the race against cancer. Cancer Discovery. 2021;11(1):45-58
  54. 54. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. The New England Journal of Medicine. 2020;382(6):545-553
  55. 55. Zhao R, Cheng L, Jiang Z, Wei X, Li B, Wu Q , et al. DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells. Oncoimmunology. 2019;8(1):e1509173
  56. 56. Ng YY, Tay JCK, Li Z, Wang J, Zhu J, Wang S. T cells expressing NKG2D CAR with a DAP12 signaling domain stimulate lower cytokine production while effective in tumor eradication. Molecular Therapy. 2021;29(1):75-85
  57. 57. Billadeau DD, Upshaw JL, Schoon RA, Dick CJ, Leibson PJ. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nature Immunology. 2003;4(6):557-564
  58. 58. Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature. 1998;391(6668):703-707
  59. 59. Topfer K, Cartellieri M, Michen S, Wiedemuth R, Muller N, Lindemann D, et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Journal of Immunology. 2015;194(7):3201-3212
  60. 60. Johnson GA, Locke FL. Mechanisms of resistance to chimeric antigen receptor T cell therapy. Hematology/Oncology Clinics of North America. 2023;37(6):1189-1199
  61. 61. Cronk RJ, Zurko J, Shah NN. Bispecific chimeric antigen receptor T cell therapy for B cell malignancies and multiple myeloma. Cancers (Basel). 2020;12(9):2523
  62. 62. Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: A phase 1 dose escalation and expansion trial. Nature Medicine. 2020;26(10):1569-1575
  63. 63. Zah E, Nam E, Bhuvan V, Tran U, Ji BY, Gosliner SB, et al. Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma. Nature Communications. 2020;11(1):2283
  64. 64. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nature Reviews. Clinical Oncology. 2020;17(3):147-167
  65. 65. Gonzalez A, Roguev A, Frankel NW, Garrison BS, Lee D, Gainer M, et al. Development of logic-gated CAR-NK cells to reduce target-mediated healthy tissue toxicities. Cancer Research. 2021;81(13):LB028
  66. 66. Muftuoglu M, Basyal M, Li L, Lv JX, Ostermann LB, Zhao R, et al. Calibrated release IL15 bivalent CD33 and/or FLT3 and NOT Emcn logic gated gene circuit CAR-NK cell therapy (SENTI-202) in venetoclax resistant patient derived xenograft acute myeloid leukemia models. Blood. 2023;142(Suppl. 1):4831
  67. 67. Gonzalez A, Hong EP, Yucel G, Leitner E, Chinta P, Deng H, et al. Preclinical development of SENTI-202, an off-the-shelf logic gated CAR-NK cell therapy, for the treatment of CD33/FLT3+hematologic malignancies including AML. Cancer Research. 2023;83(Suppl. 7):3195
  68. 68. Junca AG, Frankel N, Morvan M, Roguev A, Hung M, Gordley R, et al. Senti-401, an allogeneic logic-gated and multiarmed Car-Nk cell therapy for the treatment of Cea-expressing solid tumors with enhanced selectivity and efficacy, journal for immunotherapy of. Cancer. 2022;10:A235-A235
  69. 69. Garrison B, Deng H, Yucel G, Frankel N, Gordley R, Hung M, et al. Logic gated FLT3 or CD33 not EMCN CAR-NK cell therapy (SENTI-202) for precise targeting of AML. Molecular Therapy. 2022;30(4):398-399
  70. 70. Wallstabe L, Gottlich C, Nelke LC, Kuhnemundt J, Schwarz T, Nerreter T, et al. ROR1-CAR T cells are effective against lung and breast cancer in advanced microphysiologic 3D tumor models. JCI Insight. 2019;4(18):e126345
  71. 71. Srivastava S, Salter AI, Liggitt D, Yechan-Gunja S, Sarvothama M, Cooper K, et al. Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell. 2019;35(3):489-503.e8
  72. 72. Cho JH, Okuma A, Sofjan K, Lee S, Collins JJ, Wong WW. Engineering advanced logic and distributed computing in human CAR immune cells. Nature Communications. 2021;12(1):792
  73. 73. Sterner RC, Sterner RM. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer Journal. 2021;11(4):69
  74. 74. Mensali N, Dillard P, Hebeisen M, Lorenz S, Theodossiou T, Myhre MR, et al. NK cells specifically TCR-dressed to kill cancer cells. eBioMedicine. 2019;40:106-117
  75. 75. Wiernik A, Foley B, Zhang B, Verneris MR, Warlick E, Gleason MK, et al. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition. Clinical Cancer Research. 2013;19(14):3844-3855
  76. 76. Vallera DA, Zhang B, Gleason MK, Oh S, Weiner LM, Kaufman DS, et al. Heterodimeric bispecific single-chain variable-fragment antibodies against EpCAM and CD16 induce effective antibody-dependent cellular cytotoxicity against human carcinoma cells. Cancer Biotherapy & Radiopharmaceuticals. 2013;28(4):274-282
  77. 77. Gleason MK, Ross JA, Warlick ED, Lund TC, Verneris MR, Wiernik A, et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood. 2014;123(19):3016-3026
  78. 78. Schmohl JU, Gleason MK, Dougherty PR, Miller JS, Vallera DA. Heterodimeric bispecific single chain variable fragments (scFv) killer engagers (BiKEs) enhance NK-cell activity against CD133+ colorectal cancer cells. Targeted Oncology. 2016;11(3):353-361
  79. 79. Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood-derived NK cells facilitates CAR-like responses against CD30(+) malignancies. Clinical Cancer Research. 2021;27(13):3744-3756
  80. 80. Reusch U, Burkhardt C, Fucek I, Le Gall F, Le Gall M, Hoffmann K, et al. A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells. MAbs. 2014;6(3):728-739
  81. 81. Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clinical Cancer Research. 2016;22(14):3440-3450
  82. 82. Schmohl JU, Felices M, Oh F, Lenvik AJ, Lebeau AM, Panyam J, et al. Engineering of anti-CD133 trispecific molecule capable of inducing NK expansion and driving antibody-dependent cell-mediated cytotoxicity. Cancer Research and Treatment. 2017;49(4):1140-1152
  83. 83. Arvindam US, van Hauten PMM, Schirm D, Schaap N, Hobo W, Blazar BR, et al. A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells. Leukemia. 2021;35(6):1586-1596
  84. 84. Goebeler ME, Bargou RC. T cell-engaging therapies—BiTEs and beyond. Nature Reviews. Clinical Oncology. 2020;17(7):418-434
  85. 85. Hibler W, Merlino G, Yu Y. CAR NK cell therapy for the treatment of metastatic melanoma: Potential & prospects. Cells. 2023;12(23):2750
  86. 86. Fetzko SL, Timothy LD, Parihar R. NK cell therapeutics for hematologic malignancies: From potential to fruition. Current Hematologic Malignancy Reports. 2023;18(6):264-272
  87. 87. Gauthier L, Morel A, Anceriz N, Rossi B, Blanchard-Alvarez A, Grondin G, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell. 2019;177(7):1701-1713.e16
  88. 88. Granzin M, Wagner J, Kohl U, Cerwenka A, Huppert V, Ullrich E. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Frontiers in Immunology. 2017;8:458
  89. 89. Miller JS. Therapeutic applications: Natural killer cells in the clinic. Hematology. American Society of Hematology. Education Program. 2013;2013:247-253
  90. 90. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Science Translational Medicine. 2016;8(357):357ra123
  91. 91. Shapiro RM, Birch GC, Hu G, Vergara Cadavid J, Nikiforow S, Baginska J, et al. Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse. The Journal of Clinical Investigation. 2022;132(11):e154334
  92. 92. Gang M, Marin ND, Wong P, Neal CC, Marsala L, Foster M, et al. CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas. Blood. 2020;136(20):2308-2318
  93. 93. Dong H, Xie G, Liang Y, Ham JD, Vergara J, Chen J, et al. Engineered memory-like NK cars targeting a neoepitope derived from intracellular NPM1c exhibit potent activity and specificity against acute myeloid leukemia. Blood. 2020;136(Suppl. 1):3
  94. 94. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia. 2018;32(2):520-531
  95. 95. Lopez-Cantillo G, Uruena C, Camacho BA, Ramirez-Segura C. CAR-T cell performance: How to improve their persistence? Frontiers in Immunology. 2022;13:878209
  96. 96. Shen L, Xiao Y, Tian J, Lu Z. Remodeling metabolic fitness: Strategies for improving the efficacy of chimeric antigen receptor T cell therapy. Cancer Letters. 2022;529:139-152
  97. 97. Stojanovic A, Fiegler N, Brunner-Weinzierl M, Cerwenka A. CTLA-4 is expressed by activated mouse NK cells and inhibits NK cell IFN-gamma production in response to mature dendritic cells. Journal of Immunology. 2014;192(9):4184-4191
  98. 98. Sanseviero E, O'Brien EM, Karras JR, Shabaneh TB, Aksoy BA, Xu W, et al. Anti-CTLA-4 activates intratumoral NK cells and combined with IL15/IL15Ralpha complexes enhances tumor control. Cancer Immunology Research. 2019;7(8):1371-1380
  99. 99. Judge SJ, Dunai C, Aguilar EG, Vick SC, Sturgill IR, Khuat LT, et al. Minimal PD-1 expression in mouse and human NK cells under diverse conditions. The Journal of Clinical Investigation. 2020;130(6):3051-3068
  100. 100. Davis Z, Felices M, Lenvik T, Badal S, Walker JT, Hinderlie P, et al. Low-density PD-1 expression on resting human natural killer cells is functional and upregulated after transplantation. Blood Advances. 2021;5(4):1069-1080
  101. 101. Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. The Journal of Clinical Investigation. 2018;128(10):4654-4668
  102. 102. Dong W, Wu X, Ma S, Wang Y, Nalin AP, Zhu Z, et al. The mechanism of anti-PD-L1 antibody efficacy against PD-L1-negative tumors identifies NK cells expressing PD-L1 as a cytolytic effector. Cancer Discovery. 2019;9(10):1422-1437
  103. 103. Newman J, Horowitz A. NK cells seize PD1 from leukaemia cells. Nature Reviews. Immunology. 2021;21(6):345
  104. 104. Judge SJ, Murphy WJ, Canter RJ. Characterizing the dysfunctional NK cell: Assessing the clinical relevance of exhaustion, anergy, and senescence. Frontiers in Cellular and Infection Microbiology. 2020;10:49
  105. 105. da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunology Research. 2014;2(5):410-422
  106. 106. Chauvin JM, Ka M, Pagliano O, Menna C, Ding Q , DeBlasio R, et al. IL15 stimulation with TIGIT blockade reverses CD155-mediated NK-cell dysfunction in melanoma. Clinical Cancer Research. 2020;26(20):5520-5533
  107. 107. Sarhan D, Hippen KL, Lemire A, Hying S, Luo X, Lenvik T, et al. Adaptive NK cells resist regulatory T-cell suppression driven by IL37. Cancer Immunology Research. 2018;6(7):766-775
  108. 108. Zhang Q , Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nature Immunology. 2018;19(7):723-732
  109. 109. Ali AM, Moran MT, Tuazon J, Gyurova I, Vignali DAA, Waggoner SN. LAG-3 modulation of natural killer cell immunoregulatory function. Journal of Immunology. 2019;202(1_Supplement):7
  110. 110. Kohrt HE, Thielens A, Marabelle A, Sagiv-Barfi I, Sola C, Chanuc F, et al. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood. 2014;123(5):678-686
  111. 111. Vey M, Dumas PY, Recher C, Gastaud L, Lioure B, Bulabois CE, et al. Randomized phase 2 trial of Lirilumab (anti-KIR monoclonal antibody, mAb) as maintenance treatment in elderly patients (pts) with acute myeloid leukemia (AML): Results of the Effikir trial. Blood. 2017;130(Suppl. 1):889
  112. 112. Vey N, Karlin L, Sadot-Lebouvier S, Broussais F, Berton-Rigaud D, Rey J, et al. A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. Oncotarget. 2018;9(25):17675-17688
  113. 113. Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175(7):1731-1743.e13
  114. 114. Chames P, Van Regenmortel M, Weiss E, Baty D. Therapeutic antibodies: Successes, limitations and hopes for the future. British Journal of Pharmacology. 2009;157(2):220-233
  115. 115. Daher M, Basar R, Gokdemir E, Baran N, Uprety N, Nunez Cortes AK, et al. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood. 2021;137(5):624-636
  116. 116. Kamiya T, Seow SV, Wong D, Robinson M, Campana D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. The Journal of Clinical Investigation. 2019;129(5):2094-2106
  117. 117. Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, et al. Metabolic reprograming via deletion of CISH in human iPSC-derived NK cells promotes in vivo persistence and enhances anti-tumor activity. Cell Stem Cell. 2020;27(2):224-237.e6
  118. 118. Ni J, Wang X, Stojanovic A, Zhang Q , Wincher M, Buhler L, et al. Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1alpha unleashes NK cell activity. Immunity. 2020;52(6):1075-1087.e8
  119. 119. Nunez SY, Ziblat A, Secchiari F, Torres NI, Sierra JM, Raffo Iraolagoitia XL, et al. Human M2 macrophages limit NK cell effector functions through secretion of TGF-beta and engagement of CD85j. Journal of Immunology. 2018;200(3):1008-1015
  120. 120. Renner K, Singer K, Koehl GE, Geissler EK, Peter K, Siska PJ, et al. Metabolic hallmarks of tumor and immune cells in the tumor microenvironment. Frontiers in Immunology. 2017;8:248
  121. 121. Tumino N, Di Pace AL, Besi F, Quatrini L, Vacca P, Moretta L. Interaction between MDSC and NK cells in solid and hematological malignancies: Impact on HSCT. Frontiers in Immunology. 2021;12:638841
  122. 122. Zalfa C, Paust S. Natural killer cell interactions with myeloid derived suppressor cells in the tumor microenvironment and implications for cancer immunotherapy. Frontiers in Immunology. 2021;12:633205
  123. 123. Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunological Reviews. 2017;276(1):121-144
  124. 124. Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metabolism. 2018;27(5):977-987.e4
  125. 125. Halford S, Veal GJ, Wedge SR, Payne GS, Bacon CM, Sloan P, et al. A phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer. Clinical Cancer Research. 2023;29(8):1429-1439
  126. 126. Jin D, Fan J, Wang L, Thompson LF, Liu A, Daniel BJ, et al. CD73 on tumor cells impairs antitumor T-cell responses: A novel mechanism of tumor-induced immune suppression. Cancer Research. 2010;70(6):2245-2255
  127. 127. Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(4):1547-1552
  128. 128. Wei F, Wang D, Wei J, Tang N, Tang L, Xiong F, et al. Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance. Cellular and Molecular Life Sciences. 2021;78(1):173-193
  129. 129. Giuffrida L, Sek K, Henderson MA, Lai J, Chen AXY, Meyran D, et al. CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy. Nature Communications. 2021;12(1):3236
  130. 130. Kim TD, Lee SU, Yun S, Sun HN, Lee SH, Kim JW, et al. Human microRNA-27a* targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity. Blood. 2011;118(20):5476-5486
  131. 131. Perrot I, Michaud HA, Giraudon-Paoli M, Augier S, Docquier A, Gros L, et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Reports. 2019;27(8):2411-2425.e9
  132. 132. Shaim H, Shanley M, Basar R, Daher M, Gumin J, Zamler DB, et al. Targeting the alphav integrin/TGF-beta axis improves natural killer cell function against glioblastoma stem cells. The Journal of Clinical Investigation. 2021;131(14):e142116
  133. 133. Viel S, Marcais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, et al. TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Science Signaling. 2016;9(415):ra19
  134. 134. Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS, Messaoudene M, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Research. 2018;78(4):1003-1016
  135. 135. Yvon ES, Burga R, Powell A, Cruz CR, Fernandes R, Barese C, et al. Cord blood natural killer cells expressing a dominant negative TGF-beta receptor: Implications for adoptive immunotherapy for glioblastoma. Cytotherapy. 2017;19(3):408-418
  136. 136. Young A, Ngiow SF, Barkauskas DS, Sult E, Hay C, Blake SJ, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell. 2016;30(3):391-403
  137. 137. Micklethwaite KP, Gowrishankar K, Gloss BS, Li Z, Street JA, Moezzi L, et al. Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells. Blood. 2021;138(16):1391-1405
  138. 138. Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573(7774):430-433
  139. 139. Rurik JG, Tombacz I, Yadegari A, Mendez Fernandez PO, Shewale SV, Li L, et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022;375(6576):91-96

Written By

Tianxiang Zhang

Submitted: 12 December 2023 Reviewed: 18 December 2023 Published: 06 May 2024

© The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.