Open access peer-reviewed chapter
Abstract
Gastric cancer is one of the common malignant tumors in the gastrointestinal tract, and the treatment of gastric cancer includes the main ways such as radical resection, adjuvant chemotherapy, palliative care, and drug therapy; however, patients often have defects such as high recurrence rate, high treatment burden, and serious side effects, which impose a heavy burden on the economic and social construction and patients’ families. In recent years, novel gastric cancer treatment methods featuring tumor immunotherapy have provided new treatment strategies to improve the above-mentioned defects and increase the cure rate of patients. Natural killer cells (NK cells) are key components of the body’s intrinsic immune response and can participate in both the intrinsic and adaptive immune responses, exercising the functions of tumor killing, removing pathogenic microorganisms or abnormal cells and enhancing immunity, and thus have broad prospects for new drug development and clinical treatment. This article reviews the biological properties and functions of NK cells and their interrelationship with gastric cancer treatment, and provides a reference for clinical research.
Keywords
- NK cells
- gastric cancer
- immunotherapy
- progress
1. Introduction
Globally, the mortality rate of gastric cancer is high, with approximately 14.3/100,000 in men and 6.9/100,000 in women, with men being higher than women [1, 2]. There are significant geographical differences in the incidence of gastric cancer: it is highest in East Asia, Eastern Europe and South America and lowest in northern and southern Africa. Advanced gastric cancer can metastasise to the liver, pancreas, intestinal ducts, peritoneum, mesentery, greater omentum, esophagus, bile ducts, pelvis and lymph nodes, making treatment outcomes poor. Early diagnosis and early intervention are therefore crucial. The usual treatment for gastric cancer includes the main routes of surgery, chemotherapy and radiotherapy. However, it often has drawbacks such as high recurrence rate, heavy treatment burden and side effects, which impose a heavy burden on society, economy and patients’ families. In recent years, novel gastric cancer treatments featuring tumor immunotherapy have provided new treatment strategies to improve the above-mentioned defects and increase the cure rate of patients [3, 4]. The natural killer cell (NK) is a key cell in the body’s innate immune response. It is composed of a unique group of innate lymphocytes that can participate in both the innate and adaptive immune responses and has the intrinsic ability to recognize and eliminate virally infected and tumor cells [5, 6, 7, 8, 9]. NK cells play a key role in anti-cancer immunity due to their cytotoxic mechanisms and immune response modulating ability. 20 years ago, NK cells showed good safety and efficacy in the treatment of patients with advanced leukemia [10, 11, 12, 13]. Studies suggest that NK cell content and phenotype are significantly altered in patients with a variety of malignant hematological tumors (AML, MDS) and metastatic solid tumors (gastric cancer, lung cancer). This evidence suggests that NK cells have important research value in the management of a wide range of tumors. In recent years, with the paradigm shift and technological advances in chimeric antigen receptor (CAR) engineered passaged T cell therapy, there is confidence in NK cells as a new tool for immunotherapy. Strategies to develop NK cell-based therapies focus on enhancing the potency and persistence of NK cells through co-stimulation of signaling, checkpoint inhibition, and cytokine armor, and aim to specifically redirect NK cells to tumors through CAR expression or using splice molecules. Notably, clinical studies have shown that the proportion of NK cells in the peripheral blood of patients with stage III and IV gastric cancer is significantly lower (P < 0.05). In the clinical setting, the promising results of the first generation of NK cell therapies, which showed encouraging efficacy and a remarkable safety profile, have inspired great enthusiasm for continued innovation [14, 15, 16, 17, 18, 19]. In this paper, we review the biological properties and functions of NK cells in gastric cancer patients and their interrelationship with gastric cancer therapy, as well as the latest research progress in gastric cancer immunotherapy, to provide a reference for clinical research.
2. Tumor biological characteristics of gastric cancer
2.1 Epidemiological characteristics of gastric cancer
Gastric cancer is one of the most common tumors of the digestive tract and one of the more common cancers in terms of cancer-related morbidity and mortality worldwide. According to the latest statistics gastric cancer is the fourth most common cancer worldwide and the second most common cause of cancer death [20, 21, 22]. The treatment of gastric cancer is still based on a combination of surgical procedures. For patients with early-stage gastric cancer, the 5-year overall survival (OS) rate after treatment is 90%. However, approximately 50% of patients are already progressive at diagnosis, with approximately 40–60% of those who undergo radical resection experiencing recurrence. Approximately 30–35% of patients with gastric cancer present with distant metastases at diagnosis, yet R0 resection is unlikely to be achieved in those with peritoneal dissemination. Even when resection of metastases is feasible, patients with metastatic gastric cancer have an extremely high recurrence rate. For such patients, palliative systemic therapy is the gold standard, and median survival rarely exceeds 12 months [23, 24, 25, 26, 27, 28, 29, 30].
2.2 Risk factors for gastric cancer
Risk factors for gastric cancer include a number of aspects including geographical environment, dietary lifestyle,
2.3 Tumor microenvironment
The tumor microenvironment (TME) is the internal and external environment in which tumourigenesis, growth and metastasis are associated with tumor cells. It contains cancer cells, stromal cells and macrophages, a large number of immune cells and cells secreting factors that are recruited from a distance. Through their autocrine and paracrine actions, they alter and maintain the conditions for their own survival and development, and promote tumor growth and development. Systemic and local tissues can also limit and influence tumor development and progression through metabolic, secretory, immune, structural and functional alterations [38, 39, 40, 41]. In recent years, the tumor immune microenvironment has played a key role in the development of gastric cancer. The immune system recognizes cancer cells and inhibits tumor development and metastasis.. However, tumor cells evade immune attack and induce immunosuppressive TME through two main pathways. Firstly, cancer cells hide the expression of surface antigens to avoid recognition by cytotoxic T cells. Secondly, immune tolerance to TME is induced by the secretion of immunosuppressive molecules such as interleukin-10 and VEGF [42, 43, 44].
2.4 Importance of the immune system in gastric cancer
The development, progression and prognosis of gastric cancer are strongly related to the function of the immune system. The common immune cell components in gastric cancer tissues include T cells, B cells, DC cells, NK cells, macrophages M1 and M2, etc. [45, 46, 47]. T lymphocytes are derived from lymphatic stem cells from bone marrow, which are differentiated and matured in the thymus, and then distributed to immune organs and tissues throughout the body through lymphatic and blood circulation to perform cellular immune functions. B cells can differentiate into plasma cells when stimulated by antigens, which synthesize and secrete antibodies (immunoglobulins) and perform humoral immunity. Dendritic cells are the body’s most powerful and specialized antigen presenting cells (APC), which are highly efficient in the uptake, processing and presentation of antigens. Natural killer cells are derived from bone marrow lymphoid stem cells, which depend on the bone marrow and thymic microenvironment for their differentiation and development, and are mainly found in the bone marrow, peripheral blood, liver, spleen, lung and lymph nodes; NK cells, unlike T and B cells, lymphocytes of tumor cells and virus-infected cells, are a class of non-specific killer cells that do not require pre-sensitisation. Macrophages are differentiated from monocytes in the blood after they have penetrated blood vessels. Infection and chronic inflammation are key factors in the pathogenesis of gastric cancer, with
3. Relationship between NK cells and gastric cancer
3.1 Biological properties of NK cells
Natural killer cells are important immune cells in the body, not only in the fight against tumors, viral infections and immune regulation, but also in the development of hypersensitivity reactions and autoimmune diseases in some cases, being able to recognize target cells and kill mediators [53]. In the innate immune system, NK cells are specialized immune effector cells that are the first line of anti-tumor lymphocytes and play an important role in tumor immunosurveillance. In previous clinical studies, it has been shown that low NK cell activity correlates with higher tumor incidence and high metastasis rates. nK cells are cytotoxic to tumor cells without prior activation and can modulate various immune responses by secreting immunomodulatory cytokines and chemokines. The combination of activating and inhibiting signals regulates the antitumor effects of NK cells [54]. NK cells are mainly differentiated from CD34+ bone marrow progenitor cells and are mostly present in peripheral blood accounting for 5–10% of PBMC, while active NK are also present in lymph nodes and bone marrow but at lower levels than in peripheral blood [55]. NK cells function differently from T cells and NKT cells due to the lack of expression of TCR and CD3-related complexes. Based on the expression of surface proteins CD56 and CD16, NK cells can be divided into two categories: CD56 + CD16- (immunomodulatory, cytokine production) and CD56-CD16+ (cytotoxic). However, recent advances in high-throughput sequencing and single-cell proteogenomics have revealed that NK cells may exhibit greater phenotypic heterogeneity outside of these two subpopulations, leading to the differentiation of distinct cell populations with different cellular functions [56].
3.2 Functions of NK cells
3.2.1 Cytotoxic functions of NK cells
The killing activity of NK cells is called natural killing activity because it is not restricted by MHC and does not depend on antibodies. NK cells are rich in cytoplasm and contain large asplenophilic granules, the amount of which is positively correlated with the killing activity of NK cells, which appear early after the action of NK cells on target cells, with killing effects seen in vitro at 1 hour and in vivo at 4 hours [57]. NK cells are highly cytotoxic and trigger an effective response by releasing cytolytic particles and cytotoxic cytokines after forming an immune synapse with a target. The main mediators of killing are perforin, NK cytotoxic factor and TNF. In addition, they can recognize antibody-coated cellular γRIIIA (CD16) receptors via Fc and trigger antibody-dependent cytotoxicity (ADCC) and cytokine production. Killer cell immunoglobulin-like receptors (KIR) and natural killer group 2A (NKG2A) are two major inhibitory receptors that recognize HLA molecules [58, 59].
3.2.2 Immunomodulatory functions of NK cells
NK cells can synthesize and secrete a variety of cytokines to directly kill target cells and are also able to influence the function of B cells, T cells, dendritic cells, macrophages and neutrophils through the production of chemokines. These properties pave the way for it to play a key role in immunotherapy [60].
3.2.3 Memory function of NK cells
Natural killer cells play an important anti-tumor and anti-viral role in vivo, and recent studies have revealed that NK cells have acquired immune cell characteristics and are capable of forming immune memories. NK cell development, differentiation, homeostatic maintenance and memory formation are therefore essential for the implementation of NK cell function [61]. Early studies reported a similar memory response of NK cells in mouse models of cytomegalovirus infection, a behavior not normally associated with innate immune cells. In these studies, when stimulated with a combination of IL-12 and IL-18, mouse NK cells acquired a functional phenotype characterized by increased IFN production γ. Interestingly, after a resting phase, these cells were able to reactivate with the involvement of cytokine stimulation or activation receptors and exhibited enhanced IFNγ-like responses resembling the memory-like properties of adaptive immune cells. Later, Todd Fehniger’s group hypothesized that human NK cells should similarly have memory-like properties. Consistent with this hypothesis, their studies showed that human NK cells pre-activated with IL-12, IL-15 and IL-18 and then rested for 1–3 weeks were able to generate a strong response driven by enhanced IFNγ produced after subsequent exposure to cytokines or K562 leukemia cells. Since then, additional research groups have described similar memory-like functions in various immune settings, including the observation of such responses in humans [62, 63].
3.3 Rationale of NK cell anti-tumor
NK cells may have a more important role in immune surveillance and killing of mutated tumor cells than T cells. Patients with certain diseases, such as Chediak-Higashi or X-linked lymphoproliferative syndrome, are particularly susceptible to malignant lymphoproliferative diseases due to a deficiency in NK function [64]. The essence of tumor immunotherapy is to enhance the surveillance and clearance of tumor cells by the patient’s immune system through various means [65]. T cells and natural killer (NK) cells are the two most important effector cells that recognize and destroy tumor cells. Precise recognition of both positive signals provided by tumor antigens and negative signals provided by immune checkpoints can be used to determine tumor-specific T-cell activation. Similarly, NK cell activation is dependent on the integration of activating and inhibiting signals. Thus, disrupting the balance by blocking negative and enhancing positive signals from T and NK cells may be beneficial for cancer patients [66]. To date, many therapies have been reported for blocking T and NK cell inhibitory receptors, such as the checkpoint molecules CTLA-4 or PD-1/PD-L1. However, some evidence suggests that these strategies provide benefit to only a limited number of patients with tumors and that most patients continue to experience disease progression. To date, strategies to enhance the anti-tumor function of T cells and NK cells have yielded encouraging results. As the understanding of neoantigens presented by MHC molecules expands, research and clinical implementation of neoantigen-based therapies, including peripatetic T-cell therapies and cancer vaccines, are full of potential for clinical application [67]. The synergistic action of many NK cell surface receptors determines the NK cell state. Tumor cells can be made “invisible” to NK cells by up-regulating inhibitory signals or/and down-regulating activation signals on NK cells, and NK cell function can even be altered by altering the affinity of KIR-MHC interactions through different peptide libraries provided by MHC molecules. Interfering with activating and inhibiting signals has been used in a variety of therapeutic techniques to enhance NK cell function. However, changes in the affinity of the KIR-peptide/MHC complex interactions may occur due to different components of the peptides provided by MHC molecules in tumor cells and may require more research [68].
3.4 Application of NK cells in the treatment of gastric cancer
In gastric cancer patients, NK cells usually exhibit a dysfunctional phenotype characterized by an altered gene expression profile and reduced cytotoxic function, which reduces the feasibility of autologous NK cell therapeutic applications. In addition, the reduced number of autologous NK cells is a major cause of tumor progression. Current NK cell therapy relies on allogeneic sources, namely peripheral blood mononuclear cells, umbilical cord blood, immortalized cell lines, hematopoietic stem and progenitor cells (HSPC) and induced pluripotent stem cells (iPSC). All sources can provide clinically meaningful doses of cells suitable for CAR recipient engineering and have transitioned to human studies. However, they have unique advantages and challenges, and may have different potential transcriptional, phenotypic, and functional properties [69].
3.4.1 NK-92 cells
NK-92, the first NK cell-based immunotherapy to receive U.S. Food and Drug Administration (FDA) clinical trial approval, is a homogenous immortalized NK lymphoma cell line that can be expanded ex vivo to achieve large cell numbers. It was found that NK-92 cells can kill tumor cell lines and primary tumor cells cultured in vitro, and in addition they are not susceptible to immunosuppression, making them promising for tumor cell therapy. However, its oncogenic risk and lack of ADCC-mediated cell killing ability have limited its application [70].
3.4.2 NK cells after in vitro differentiation of CD34+ progenitor cells
Dolstra et al. showed in their trial that transfer of HSPC-NK cells into elderly patients with acute myelogenous leukemia (AML) resulted in better outcomes. However, the safety and efficacy of its application in other tumors needs further validation. Future work will also need to address whether HSPC-NK cells can be effectively designed to achieve enhanced tumor specificity [71].
3.4.3 NK cells after differentiation of iPSCs
Induced pluripotent stem cells (iPSCs) have played an important role in disease modeling, drug discovery and cell therapy, and have contributed to the development of the disciplines of cell biology and regenerative medicine. Currently, iPSCs technology has become an important tool in the study of pathological mechanisms, new drugs are being developed using iPSCs technology, and the number of clinical trials using iPSCs-derived cells is growing. iPSCs are an attractive source of NK cells because of their clonal growth and high expansion capacity, as well as their ability to differentiate in vitro, allowing the manufacture of a large number of homogeneous NK cell products. A potential drawback is that iPSC-derived NK cells typically express low levels of endogenous CD16, although this can be mitigated by genetic engineering. Another possible concern is that iPSCs may have a DNA methylation profile consistent with their somatic cellular tissue origin. This “epigenetic memory” may affect the development of specific cell lineages that differ from the donor cells and should be considered when using iPSC platforms. Nevertheless, a growing number of genetically engineered iPSC-NK cell candidates are emerging from preclinical studies, some of which have already transitioned to clinical trials [72].
3.4.4 NK cells from peripheral blood or from umbilical cord blood
Primary NK cells can be collected from peripheral blood (PB-NK cells) or from umbilical cord blood (CB-NK cells.) CB-NK cells can be readily available frozen through blood banks, whereas PB-NK cells require single harvest and donor-specific collection from healthy donors. in 2005, in work led by Dario Campana, PB-NK cells served as the first successful CAR construct platform for somatic introduction into NK cells, and today, PB-NK cells provide the basis for a variety of current products [73].
4. Conclusion
Immunotherapy is a novel and effective therapeutic strategy that has emerged as a new hope for many patients with gastric cancer. Although NK cell-based immunotherapy is considered to be a safe off-the-shelf antitumor therapy, important issues remain resolved and still a large proportion of gastric cancer patients do not benefit from immunotherapeutic agents. With the development of immunotherapy, it will be important to study the abnormal alterations in the biological phenotype and transcriptomic profile of NK cells, the NK cell subsets and their interrelationship with the prognosis of gastric cancer patients, and to elucidate the key parameters that determine the potency and persistence of NK cells. In addition, to maximize the lifespan and expand the efficacy of NK cells, multiple therapeutic strategies need to be combined [74]. Finally, to ensure NK cell quality, methods for NK cell proliferation and preservation need to be optimized. We believe that great breakthroughs will be achieved in the future in the study of NK cells for immunotherapy of gastric cancer.
Acknowledgments
The authors would like to thank the members in National Postdoctoral Research Station of Gansu Provincial Hospital, Institute of Biology & Hefei Institute of Physical Science, Chinese Academy of Sciences, and Institute of Health-Biotech, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd. for their technical support. We also thank the staff in Beijing Yunwei Biotechnology Development Co., LTD for their language editing service. This study was supported by the following fund projects: Key Laboratory of Gastrointestinal Tumor Diagnosis and Treatment of National Health and Health Commission (2019PT320005); the National Natural Science Foundation of China (82260031); Key Laboratory of Molecular Diagnosis and Precision Therapy of Surgical Tumors in Gansu Province (18JR2RA033); Gansu Provincial Key Talent Project of Gansu Provincial Party Committee Organization Department (2020RCXM076); Basic Research Innovation Group of Gansu Province (22JR5RA709); Natural Science Foundation of Gansu Province (21JR11RA186, 20JR10RA415); Gansu Provincial Hospital Intra-Hospital Research Fund Project (21GSSYB-8, 20GSSY5-2); The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1); China Postdoctoral Science Foundation (2019 M661033), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), the National Science and Technology Major Projects of China for “Major New Drugs Innovation and Development” (2014ZX09508002-003), Major Program of the National Natural Science Foundation of China (81330015), the project Youth Fund funded by Shandong Provincial Natural Science Foundation (ZR2020QC097), Natural Science Foundation of Tianjin (19JCQNJC12500), Jiangxi Provincial Novel Research & Development Institutions of Shangrao City (2020AB002), Jiangxi Provincial Natural Science Foundation (20224BAB206077, 20212BAB216073), Jiangxi Provincial Key New Product Incubation Program from Technical Innovation Guidance Program of Shangrao City (2020G002).
Appendices and nomenclature
natural killer cells acute myeloid leukemia myelodysplastic syndromes chimeric antigen receptor overall survival Epstein-Barr virus microsatellite instability mismatch repair tumor microenvironment regulatory T cells myeloid-derived suppressor cells cytotoxic T lymphocyte-associated protein 4 programmed death protein 1 programmed cell death ligand-1 T cell immunoglobulin and mucin-containing structural domain 3 antibody-dependent cytotoxicity Killer cell immunoglobulin-like receptors natural killer group 2A immunoreceptor tyrosine-based inhibitory motifs hematopoietic stem and progenitor cells Food and Drug Administration peripheral blood NK cells umbilical cord blood NK cells
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