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Qiu Z, Li Z, Zhang C, Zhao Q, Liu Z, Cheng Q, Zhang J, Lin A, Luo P. NK Cell Senescence in Cancer: From Molecular Mechanisms to Therapeutic Opportunities. Aging Dis 2025:AD.2025.0053. [PMID: 40249925 DOI: 10.14336/ad.2025.0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2025] [Accepted: 03/13/2025] [Indexed: 04/20/2025] Open
Abstract
P Natural killer (NK) cells function as crucial effectors in the innate immune response against tumors. Nevertheless, NK cell senescence, characterized by phenotypic and functional changes, substantially compromises their antitumor immune response. This review provides a comprehensive summary of the molecular mechanisms governing NK cell senescence and its implications for cancer immunotherapy. We propose a refined definition of NK cell senescence based on distinct biomarkers, including elevated CD57 expression, reduced cytotoxicity, and altered cytokine secretion. Moreover, we investigate the complex interactions between the tumor microenvironment (TME) and NK cell senescence, highlighting the influence of chronic inflammation, immunosuppressive cytokines, and persistent tumor antigenic stimulation. Additionally, this review underscores the potential utility of senescent NK cells as biomarkers for assessing antitumor efficacy and examines the adverse effects of NK cell senescence on cancer immunotherapy. Lastly, we summarize current approaches to mitigate NK cell senescence, such as gene editing techniques and cytokine modulation, which may enhance the efficacy of NK cell-based immunotherapies. By establishing a comprehensive framework for understanding NK cell senescence within the TME, this review aims to guide future research and the development of innovative therapeutic strategies targeting senescent NK cells to improve cancer immunotherapy outcomes.
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Affiliation(s)
- Zilin Qiu
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Zhengrui Li
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Cangang Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qun Zhao
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Big data analysis and mining application for precise diagnosis and treatment of gastric cancer Hebei Provincial Engineering Research Center, Shijiazhuang 050011, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Quan Cheng
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Anqi Lin
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Peng Luo
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
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Ashrafi S, Amini AA, Karimi P, Bagherian M, Adibzadeh Sereshgi MM, Asgarhalvaei F, Ahmadi K, Yazdi MH, Jahantigh HR, Mahdavi M, Sarrami Forooshani R. Candidiasis in breast cancer: Tumor progression or not? IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:1346-1356. [PMID: 39386227 PMCID: PMC11459349 DOI: 10.22038/ijbms.2024.75408.16379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 04/06/2024] [Indexed: 10/12/2024]
Abstract
Candida albicans is an "opportunistic fungal agent" in cancer patients that can become colonized in both mucosal and deep tissues and cause severe infections. Most evidence has shown that C. albicans can enhance the progress of different cancers by several mechanisms such as generating virulence factors, participation in endogenous production of pro-inflammatory mediators, and stimulating a wide range of immune cells in the host. The main idea of this review is to describe a range of Candida-used mechanisms that are important in candidiasis-associated malignant processes and cancer development, particularly breast cancer. This review intends to provide a detailed discussion on different regulatory mechanisms of C. albicans that undoubtedly help to open new therapeutic horizons of cancer therapy in patients with fungal infection. The current therapeutic approach is not fully effective in immunocompromised and cancer patients, and further studies are required to find new products with effective antifungal properties and minimal side effects to increase the susceptibility of opportunistic fungal infections to conventional antifungal agents. So, in this situation, a special therapy should be considered to control the infection and simultaneously have the most therapeutic index on tumor patients.
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Affiliation(s)
- Somayeh Ashrafi
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Recombinant Vaccine Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, (IAUPS), Tehran, Iran
- These authors contributed eqully to this work
| | - Abbas Ali Amini
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Pegah Karimi
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Biochemistry, Faculty of Basic Sciences, Islamic Azad University, Central Tehran Branch, Tehran, Iran
- These authors contributed eqully to this work
| | - Maryam Bagherian
- Department of Hematology and Oncology and Stem Cell Transplantation, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Asgarhalvaei
- Department of Microbiology, Faculty of Advanced Sciences & Technology, Tehran Medical Sciences, Islamic Azad University, (IAUPS), Tehran, Iran
| | - Khadijeh Ahmadi
- Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mohammad Hossein Yazdi
- Recombinant Vaccine Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Immunotherapy Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Jahantigh
- Animal Health and Zoonosis PhD Course, Department of Veterinary Medicine, University of Bari, Bari, Italy
| | - Mehdi Mahdavi
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Recombinant Vaccine Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Immunotherapy Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Sarrami Forooshani
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
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Fan Z, Han D, Fan X, Zhao L. Ovarian cancer treatment and natural killer cell-based immunotherapy. Front Immunol 2023; 14:1308143. [PMID: 38187402 PMCID: PMC10768003 DOI: 10.3389/fimmu.2023.1308143] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/04/2023] [Indexed: 01/09/2024] Open
Abstract
Background Ovarian cancer (OC) is one of the malignant tumors that poses a serious threat to women's health. Natural killer (NK) cells are an integral part of the immune system and have the ability to kill tumor cells directly or participate indirectly in the anti-tumor immune response. In recent years, NK cell-based immunotherapy for OC has shown remarkable potential. However, its mechanisms and effects remain unclear when compared to standard treatment. Methods To explore the value of NK cell-based immunotherapy in the treatment of OC, we conducted a literature review. In comparison to standard treatment, our focus was primarily on the current anti-tumor mechanisms, the clinical effect of NK cells against OC, factors affecting the structure and function of NK cells, and strategies to enhance the effectiveness of NK cells. Results We found that NK cells exert their therapeutic effects in OC through mechanisms such as antibody-dependent cell cytotoxicity, perforin release, and granule enzyme secretion. They also secrete IFN-γ and TNF-α or engage in Fas/FasL and TRAIL/TRAILR pathways, mediating the death of OC cells. In clinical trials, the majority of patients experienced disease stability with mild side effects after receiving NK cell-based immunotherapy, but there is still a lack of high-quality research evidence regarding its clinical effectiveness. OC and prior experience with standard treatments have an effect on NK cells, and it may be considered to maximize NK cell effects through the modulation of the tumor microenvironment or combination with other therapies. Conclusions In this review, we have summarized the current evidence of NK cell applications in the treatment of OC. Furthermore, factors and strategies that influence and enhance the role of NK cell immunotherapy are discussed.
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Affiliation(s)
- Zhongru Fan
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Dongyu Han
- Department of Obstetrics and Gynecology, Suzhou Hospital, Affiliated Hospital of Meddical School, Nanjing University, Suzhou, China
| | - Xin Fan
- Department of Radiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lin Zhao
- Department of Obstetrics and Gynecology, Suzhou Hospital, Affiliated Hospital of Meddical School, Nanjing University, Suzhou, China
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Zheng S, Li H, Li Y, Chen X, Shen J, Chen M, Zhang C, Wu J, Sun Q. The emerging role of glycolysis and immune evasion in gastric cancer. Cancer Cell Int 2023; 23:317. [PMID: 38071310 PMCID: PMC10710727 DOI: 10.1186/s12935-023-03169-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/27/2023] [Indexed: 08/21/2024] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Similar to other types of tumors, GC cells undergo metabolic reprogramming and switch to a "predominantly glycolytic" metabolic pattern to promote its survival and metastasis, also known as "the Warburg effect", which is characterized by enhanced glucose uptake and lactate production. A large number of studies have shown that targeting cancer cells to enhanced glycolysis is a promising strategy, that can make cancer cells more susceptible to other conventional treatment methods of treatment, including chemotherapy, radiotherapy and immunotherapy, and so on. Therefore, this review summarizes the metabolic characteristics of glycolysis in GC cells and focuses on how abnormal lactate concentration can lead to immunosuppression through its effects on the differentiation, metabolism, and function of infiltrating immune cells, and how targeting this phenomenon may be a potential strategy to improve the therapeutic efficacy of GC.
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Affiliation(s)
- Shanshan Zheng
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Huaizhi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Yaqi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Xu Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Junyu Shen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Menglin Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Cancan Zhang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
- No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Jian Wu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
| | - Qingmin Sun
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
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Zhang Y, Zhou W, Yang J, Yang J, Wang W. Chimeric antigen receptor engineered natural killer cells for cancer therapy. Exp Hematol Oncol 2023; 12:70. [PMID: 37563648 PMCID: PMC10413722 DOI: 10.1186/s40164-023-00431-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 07/27/2023] [Indexed: 08/12/2023] Open
Abstract
Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers of stressed and transformed cells. Based on their potent capacity to kill cancer cells and good tolerance of healthy cells, NK cells have been successfully employed in adoptive cell therapy to treat cancer patients. In recent years, the clinical success of chimeric antigen receptor (CAR)-T cells has proven the vast potential of gene-manipulated immune cells as the main force to fight cancer. Following the lessons learned from mature gene-transfer technologies and advanced strategies in CAR-T therapy, NK cells have been rapidly explored as a promising candidate for CAR-based therapy. An exponentially growing number of studies have employed multiple sources of CAR-NK cells to target a wide range of cancer-related antigens, showing remarkable outcomes and encouraging safety profiles. Clinical trials of CAR-NK cells have also shown their impressive therapeutic efficacy in the treatment of hematological tumors, but CAR-NK cell therapy for solid tumors is still in the initial stages. In this review, we present the favorable profile of NK cells as a potential platform for CAR-based engineering and then summarize the outcomes and strategies of CAR-NK therapies in up-to-date preclinical and clinical investigations. Finally, we evaluate the challenges remaining in CAR-NK therapy and describe existing strategies that can assist us in devising future prospective solutions.
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Affiliation(s)
- Yalan Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Weilin Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Jiangping Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
- Department of Head and Neck Oncology and Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Jinrong Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
- Hematology Research Laboratory, Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Wei Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China.
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D’Silva SZ, Singh M, Pinto AS. NK cell defects: implication in acute myeloid leukemia. Front Immunol 2023; 14:1112059. [PMID: 37228595 PMCID: PMC10203541 DOI: 10.3389/fimmu.2023.1112059] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
Acute Myeloid Leukemia (AML) is a complex disease with rapid progression and poor/unsatisfactory outcomes. In the past few years, the focus has been on developing newer therapies for AML; however, relapse remains a significant problem. Natural Killer cells have strong anti-tumor potential against AML. This NK-mediated cytotoxicity is often restricted by cellular defects caused by disease-associated mechanisms, which can lead to disease progression. A stark feature of AML is the low/no expression of the cognate HLA ligands for the activating KIR receptors, due to which these tumor cells evade NK-mediated lysis. Recently, different Natural Killer cell therapies have been implicated in treating AML, such as the adoptive NK cell transfer, Chimeric antigen receptor-modified NK (CAR-NK) cell therapy, antibodies, cytokine, and drug treatment. However, the data available is scarce, and the outcomes vary between different transplant settings and different types of leukemia. Moreover, remission achieved by some of these therapies is only for a short time. In this mini-review, we will discuss the role of NK cell defects in AML progression, particularly the expression of different cell surface markers, the available NK cell therapies, and the results from various preclinical and clinical trials.
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Affiliation(s)
- Selma Z. D’Silva
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Meenakshi Singh
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Andrea S. Pinto
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
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Mercogliano MF, Bruni S, Mauro FL, Schillaci R. Emerging Targeted Therapies for HER2-Positive Breast Cancer. Cancers (Basel) 2023; 15:cancers15071987. [PMID: 37046648 PMCID: PMC10093019 DOI: 10.3390/cancers15071987] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.
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Firouzi J, Hajifathali A, Azimi M, Parvini N, Ghaemi F, Shayan Asl N, Hedayati Asl AA, Safa M, Ebrahimi M. Hsp70, in Combination with IL-15 and PD-1 Blocker, Interferes with The Induction of Cytotoxic NK Cells in Relapsed Acute Myeloid Leukemia Patients. CELL JOURNAL 2023; 25:92-101. [PMID: 36840455 PMCID: PMC9968373 DOI: 10.22074/cellj.2023.561054.1123] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Indexed: 02/26/2023]
Abstract
OBJECTIVE Natural killer (NK) cells are critical immune cells for acute myeloid leukemia (AML) targeting. However, little is known about the relationship between using checkpoint inhibitors and heat shock protein 70 (Hsp70) as NK cell activators to control AML. Therefore, the study aims to find the best formulation of Hsp70, human PD-1 (Programmed cell death protein 1) blocker, and interleukin 15 (IL-15) to activate NK cells against AML. MATERIALS AND METHODS In this experimental study, the NK cells were isolated from mononuclear cells (MNCs) by using magnetic activation cell sorting (MACS) and were activated using the different combinations of Hsp70, PD-1 blocker, and IL-15 and then followed by immunophenotyping, functional assays to estimate their killing potential, and evaluation of expression pattern of PRF1, PIK3CB, PD-1, AKT-1, FAS-L, TRAIL, and GER A and B. RESULTS The expression of PD-1 was significantly (P<0.05) reduced after NK cell activation by the different formulas of IL-15, Hsp70, and PD-1 blocker. The expression of NKG2A in the treated NK cells was reduced particularly in the IL-15 (P<0.01) and IL-15+PD-1 blocker (P<0.05) groups. The addition of Hsp70 increased its expression. The cytotoxic effect of NK cells increased in all groups, especially in IL-15+PD-1 blocker besides increasing interferon-gamma (IFN-γ), Granzymes, and perforin expression (P<0.05). All IL-15+PD-1 blocker group changes were associated with the upregulation of PIK3CB and AKT-1 as key factors of NK cell activation. The presence of Hsp70 reduced IFN-γ releasing, and down-regulation of PIK3CB, AKT-1, Granzymes, and Perforin (P<0.05). CONCLUSION We suggested the combination of IL-15 and PD-1 blocker could enhance the killing potential of AMLNK cells. Moreover, Hsp70 in combination with IL-15 and PD-1 blocker interferes activation of AML-NK cells through unknown mechanisms.
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Affiliation(s)
- Javad Firouzi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University
of Medical Sciences, Tehran, Iran,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran,Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Hajifathali
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran
| | - Neda Parvini
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences,
Kurdistan, Iran
| | - Fatemeh Ghaemi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran
| | - Niloufar Shayan Asl
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran
| | - Amir Abbas Hedayati Asl
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran
| | - Majid Safa
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University
of Medical Sciences, Tehran, Iran,Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran,Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran,P.O.Box: 1449614535Department of Hematology
and Blood BankingFaculty of Allied MedicineIran University of Medical
SciencesTehranIranP.O.Box: 16635-148Department of Stem Cells and Developmental BiologyCell
Science Research CenterRoyan Institute for Stem Cell Biology and TechnologyACECRTehranIran
Emails: ,
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and
Technology, ACECR, Tehran, Iran,Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology,
ACECR, Tehran, Iran,P.O.Box: 1449614535Department of Hematology
and Blood BankingFaculty of Allied MedicineIran University of Medical
SciencesTehranIranP.O.Box: 16635-148Department of Stem Cells and Developmental BiologyCell
Science Research CenterRoyan Institute for Stem Cell Biology and TechnologyACECRTehranIran
Emails: ,
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Abstract
INTRODUCTION New methods in cancer immunotherapy, such as chimeric antigen receptor (CAR)-T cells, have shown promising results in destroying malignant cells. However, limitations and side effects of CAR-T cell therapy, such as graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome, have motivated researchers to investigate safer alternative cells like natural killer (NK) cells. AREA COVERED NK cells can effectively recognize hematologic malignant cells and destroy them. Many clinical and preclinical studies investigate the efficacy of CAR-NK cells in treating lymphoma and other hematologic malignancies. The results of published clinical trials and preclinical studies have shown that CAR-NK cells could be an appropriate choice for treating lymphoma. In this review, we discuss the characteristics of CAR-NK cells, their role in treating B-cell and T-cell lymphoma, and the challenges faced by using them. We also highlight clinical trials using CAR-NK cells for treating lymphoma. EXPERT OPINION CAR-NK cells have shown promising results in cancer therapy, especially B-cell lymphoma, with a much lower risk for GVHD, cytokine release syndrome, and neurotoxicity than CAR-T cells. Further investigations are required to overcome the obstacles of CAR-NK cell therapy, both generally, and in cancers like T-cell lymphoma.
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Affiliation(s)
- Shaghayegh Khanmohammadi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Qin H, You C, Yan F, Tan K, Xu C, Zhao R, Ekpo MD, Tan S. Overcoming the challenges in translational development of natural killer cell therapeutics: An opinion paper. Front Oncol 2022; 12:1062765. [DOI: 10.3389/fonc.2022.1062765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/22/2022] [Indexed: 12/04/2022] Open
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Wang X, Yang X, Yuan X, Wang W, Wang Y. Chimeric antigen receptor-engineered NK cells: new weapons of cancer immunotherapy with great potential. Exp Hematol Oncol 2022; 11:85. [PMID: 36324149 PMCID: PMC9628181 DOI: 10.1186/s40164-022-00341-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/29/2022] [Indexed: 11/18/2022] Open
Abstract
Chimeric antigen receptor (CAR)-engineered T (CAR-T) cells have obtained prominent achievement in the clinical immunotherapy of hematological malignant tumors, leading to a rapid development of cellular immunotherapy in cancer treatment. Scientists are also aware of the prospective advantages of CAR engineering in cellular immunotherapy. Due to various limitations such as the serious side effects of CAR-T therapy, researchers began to investigate other immune cells for CAR modification. Natural killer (NK) cells are critical innate immune cells with the characteristic of non-specifically recognizing target cells and with the potential to become "off-the-shelf" products. In recent years, many preclinical studies on CAR-engineered NK (CAR-NK) cells have shown their remarkable efficacy in cancer therapy and their superiority over autologous CAR-T cells. In this review, we summarize the generation, mechanisms of anti-tumor activity and unique advantages of CAR-NK cells, and then analyze some challenges and recent clinical trials about CAR-NK cells therapy. We believe that CAR-NK therapy is a promising prospect for cancer immunotherapy in the future.
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Affiliation(s)
- Xiao Wang
- grid.16821.3c0000 0004 0368 8293Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Xuejiao Yang
- grid.16821.3c0000 0004 0368 8293Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Xiang Yuan
- grid.13291.380000 0001 0807 1581Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Wenbo Wang
- grid.24516.340000000123704535Department of Oncology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072 China
| | - Yueying Wang
- grid.16821.3c0000 0004 0368 8293Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
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12
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Li H, Song W, Li Z, Zhang M. Preclinical and clinical studies of CAR-NK-cell therapies for malignancies. Front Immunol 2022; 13:992232. [PMID: 36353643 PMCID: PMC9637940 DOI: 10.3389/fimmu.2022.992232] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/13/2022] [Indexed: 12/01/2022] Open
Abstract
The development of chimeric antigen receptor T (CAR-T) cell therapy, a specific type of immunotherapy, in recent decades was a fantastic breakthrough for the treatment of hematological malignancies. However, difficulties in collecting normal T cells from patients and the time cost of manufacturing CAR-T cells have limited the application of CAR-T-cell therapy. In addition, the termination of related clinical trials on universal CAR-T cell therapy has made further research more difficult. Natural killer (NK) cells have drawn great attention in recent years. Chimeric antigen receptor-NK (CAR-NK) cell therapy is a promising strategy in the treatment of malignant tumors because of its lack of potential for causing graft-versus-host disease (GVHD). In this review, we will address the advances in and achievements of CAR-NK cell therapy.
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Affiliation(s)
- Hongwen Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wenting Song
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment and Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Mingzhi Zhang,
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13
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BST2, a Novel Inhibitory Receptor, Is Involved in NK Cell Cytotoxicity through Its Cytoplasmic Tail Domain. Int J Mol Sci 2022; 23:ijms231911395. [PMID: 36232695 PMCID: PMC9570199 DOI: 10.3390/ijms231911395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/16/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
Bone Marrow Stromal Cell Antigen 2 (BST2) is a type II transmembrane protein expressed on various cell types that tethers the release of viruses. Natural killer (NK) cells express low levels of BST2 under normal conditions but exhibit increased expression of BST2 upon activation. In this study, we show for the first time that murine BST2 can control the cytotoxicity of NK cells. The cytoplasmic tail of murine BST2 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM). The absence of BST2 on NK cells can enhance their cytotoxicity against tumor cells compared to wild type NK cells. NK cells isolated from NZW mice, which express ITIM-deficient BST2, also showed higher cytotoxicity than wild type NK cells. In addition, we found that galectin-8 and galectin-9 were ligands of BST2, since blocking galectin-8 or -9 with monoclonal antibodies enhanced the cytotoxicity of NK cells. These results suggested that BST2 might be a novel NK cell inhibitory receptor as it was involved in regulating NK cell cytotoxicity through its interaction with galectins.
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14
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Studying the Anticancer Effects of Thymoquinone on Breast Cancer Cells through Natural Killer Cell Activity. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9218640. [PMID: 36199754 PMCID: PMC9527111 DOI: 10.1155/2022/9218640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 12/24/2022]
Abstract
Cancer immunotherapy is quickly growing and can now be viewed as the “fifth column” of cancer treatment. In addition, cancer immunotherapy has shown promising results with different kinds of cancers and may be used as a complementary therapy with various types of treatments. Thus, “immuno-oncology” is showing astounding advantages. However, one of the main challenges that face this type of therapy is that cancer cells can evade immune system elimination through different mechanisms. Many studies were done to overcome this issue including adding immune stimulants to generate synergistic effects or by genetically modifying NK cells themselves to be stronger and more resistant. Nigella sativa, also known as black cumin, is a well-known example of a widely applicable herbal medicine. It can effectively treat a variety of diseases, such as hypertension, diabetes, bronchitis, gastrointestinal upset, and cancer. The anticancer qualities of Nigella sativa appear to be mediated by an immune-modulatory effect that stimulates human natural killer (NK) cells. These are a type of lymphocyte and first line of defense against pathogens. Objectives. In this study, we investigated the therapeutic effect of thymoquinone, a major component of Nigella sativa, on the cytotoxic pathways of NK cells. Methods. NK cells were cultured with breast cancer cell line Michigan Cancer Foundation-7 (MCF-7); and were treated with Thymoquinone. The cytotoxicity of NK cells on cancer cells was measured. The cultured media were then collected and measured via enzyme-linked immunosorbent assay (ELISA) for concentrations of perforin, granzyme B and interferon-α (IFN-α). Results. The cytotoxic effect of NK cells on tumor cells was increased in the presence of thymoquinone, with an increased release of perforin, granzyme B, and IFN-α. Conclusion. Thymoquinone promotes the cytotoxic activity of NK cells against breast cancer MCF-7 cells.
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15
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Agnarelli A, Vella V, Samuels M, Papanastasopoulos P, Giamas G. Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications. Cancers (Basel) 2022; 14:cancers14184378. [PMID: 36139540 PMCID: PMC9496849 DOI: 10.3390/cancers14184378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023] Open
Abstract
Simple Summary Gastric cancer is one of the most common malignant tumours worldwide, with the fifth and third highest morbidity and mortality, respectively, of all cancers. Survival is limited, as most of the patients are diagnosed at an advanced stage, and are not suitable for surgery with a curative intent. Chemotherapy has only modestly improved patients’ outcomes and is mainly given with a palliative intent. Immunotherapy has improved overall survival of patients with gastric cancer, and has thus become a new standard of care in clinic. In this review we discuss the strong molecular rationale for the administration of immunotherapy in this disease and analyse the clinical data supporting its use. Abstract Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.
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16
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Hervás-Salcedo R, Martín-Antonio B. A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments. Cancers (Basel) 2022; 14:3796. [PMID: 35954459 PMCID: PMC9367481 DOI: 10.3390/cancers14153796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023] Open
Abstract
Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associated with a good prognosis in MM patients and have served as the basis for developing different immunotherapy strategies. However, MM cells and other cells in the BM can polarize their phenotype and activity, creating an immunosuppressive environment where immune cells do not perform their cytotoxic activity properly, promoting tumor progression. Understanding cell-cell interactions in the BM and their impact on MM proliferation and the performance of tumor surveillance will help in designing efficient anti-MM therapies. Here, we take a journey through the BM, describing the interactions of MM cells with cells of the non-hematological and hematological compartment to highlight their impact on MM progression and the development of novel MM treatments.
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Affiliation(s)
| | - Beatriz Martín-Antonio
- Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz (IIS-FJD), University Autonomous of Madrid (UAM), 28040 Madrid, Spain
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17
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Nikoo M, Rudiansyah M, Bokov DO, Jainakbaev N, Suksatan W, Ansari MJ, Thangavelu L, Chupradit S, Zamani A, Adili A, Shomali N, Akbari M. Potential of chimeric antigen receptor (CAR)-redirected immune cells in breast cancer therapies: Recent advances. J Cell Mol Med 2022; 26:4137-4156. [PMID: 35762299 PMCID: PMC9344815 DOI: 10.1111/jcmm.17465] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/16/2022] [Accepted: 05/28/2022] [Indexed: 11/29/2022] Open
Abstract
Despite substantial developments in conventional treatments such as surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of cancer mortality in women. Currently, chimeric antigen receptor (CAR)-redirected immune cell therapy has emerged as an innovative immunotherapeutic approach to ameliorate survival rates of breast cancer patients by eliciting cytotoxic activity against cognate tumour-associated antigens expressing tumour cells. As a crucial component of adaptive immunity, T cells and NK cells, as the central innate immune cells, are two types of pivotal candidates for CAR engineering in treating solid malignancies. However, the biological distinctions between NK cells- and T cells lead to differences in cancer immunotherapy outcomes. Likewise, optimal breast cancer removal via CAR-redirected immune cells requires detecting safe target antigens, improving CAR structure for ideal immune cell functions, promoting CAR-redirected immune cells filtration to the tumour microenvironment (TME), and increasing the ability of these engineered cells to persist and retain within the immunosuppressive TME. This review provides a concise overview of breast cancer pathogenesis and its hostile TME. We focus on the CAR-T and CAR-NK cells and discuss their significant differences. Finally, we deliver a summary based on recent advancements in the therapeutic capability of CAR-T and CAR-NK cells in treating breast cancer.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of MedicineKermanshah University of Medical SciencesKermanshahIran
| | - Mohammad Rudiansyah
- Division of Nephrology & Hypertension, Department of Internal Medicine, Faculty of MedicineUniversitas Lambung Mangkurat / Ulin HospitalBanjarmasinIndonesia
| | - Dmitry Olegovich Bokov
- Institute of PharmacySechenov First Moscow State Medical UniversityMoscowRussian Federation
- Laboratory of Food ChemistryFederal Research Center of Nutrition, Biotechnology and Food SafetyMoscowRussian Federation
| | | | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical ScienceChulabhorn Royal AcademyBangkokThailand
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of PharmacyPrince Sattam Bin Abdulaziz UniversityAl‐kharjSaudi Arabia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical ScienceSaveetha UniversityChennaiIndia
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical SciencesChiang Mai UniversityChiang MaiThailand
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina HospitalShiraz University of Medical SciencesShirazIran
| | - Ali Adili
- Department of OncologyTabriz University of Medical SciencesTabrizIran
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South FloridaTampaFloridaUSA
| | - Navid Shomali
- Department of ImmunologyTabriz University of Medical SciencesTabrizIran
| | - Morteza Akbari
- Department of ImmunologyTabriz University of Medical SciencesTabrizIran
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18
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Baghery Saghchy Khorasani A, Yousefi AM, Bashash D. CAR NK cell therapy in hematologic malignancies and solid tumors; obstacles and strategies to overcome the challenges. Int Immunopharmacol 2022; 110:109041. [PMID: 35839565 DOI: 10.1016/j.intimp.2022.109041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 02/08/2023]
Abstract
Adoptive cell treatment (ACT) utilizing chimeric antigen receptors (CAR) diverts the specificity of safe cells against a target-specific antigen and portrays exceptional potential for cancer treatment. While CAR T cell treatment has risen as a breakthrough with unprecedented results within the therapeutic procedures of human malignancies, different deficiencies including challenging and costly generation processes, strict patient qualification criteria, and undesirable toxicity have ruined its application. Unlike T cells, the application of natural killer (NK) cells has attracted consideration as a reasonable alternative owing to the major histocompatibility complex (MHC)-independency, shorter life expectancy, the potential to create an off-the-shelf immune product, and potent antitumor properties. In this article, we provide an updated review of the differences between CAR T and CAR NK cells, current enhancements in CAR NK design, the available sources for collecting NK cells, and strategies for the transduction step of the CARs to NK cells. Furthermore, we focus on the published and ongoing preclinical and clinical studies of CAR NK treatment strategies both in hematologic malignancies and solid tumors. We also discuss limitations and plausible solutions to improve the perseverance, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.
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Affiliation(s)
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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19
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The tricks for fighting against cancer using CAR NK cells: A review. Mol Cell Probes 2022; 63:101817. [DOI: 10.1016/j.mcp.2022.101817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 01/07/2023]
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20
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Fereydouni M, Motaghed M, Ahani E, Kafri T, Dellinger K, Metcalfe DD, Kepley CL. Harnessing the Anti-Tumor Mediators in Mast Cells as a New Strategy for Adoptive Cell Transfer for Cancer. Front Oncol 2022; 12:830199. [PMID: 35433433 PMCID: PMC9009255 DOI: 10.3389/fonc.2022.830199] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
The emergence of cancer immunotherapies utilizing adoptive cell transfer (ACT) continues to be one of the most promising strategies for cancer treatment. Mast cells (MCs) which occur throughout vascularized tissues, are most commonly associated with Type I hypersensitivity, bind immunoglobin E (IgE) with high affinity, produce anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF), and generally populate the tumor microenvironments. Yet, the role of MCs in cancer pathologies remains controversial with evidence for both anti-tumor and pro-tumor effects. Here, we review the studies examining the role of MCs in multiple forms of cancer, provide an alternative, MC-based hypothesis underlying the mechanism of therapeutic tumor IgE efficacy in clinical trials, and propose a novel strategy for using tumor-targeted, IgE-sensitized MCs as a platform for developing new cellular cancer immunotherapies. This autologous MC cancer immunotherapy could have several advantages over current cell-based cancer immunotherapies and provide new mechanistic strategies for cancer therapeutics alone or in combination with current approaches.
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Affiliation(s)
- Mohammad Fereydouni
- Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina Greensboro (UNCG), Greensboro, NC, United States
| | - Mona Motaghed
- Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina A&T State University, Greensboro, NC, United States
| | - Elnaz Ahani
- Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina A&T State University, Greensboro, NC, United States
| | - Tal Kafri
- Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kristen Dellinger
- Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina A&T State University, Greensboro, NC, United States
| | - Dean D. Metcalfe
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christopher L. Kepley
- Department of Molecular and Cellular Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, VA, United States
- *Correspondence: Christopher L. Kepley,
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21
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Cell-based immunotherapies in gynecologic cancers. Curr Opin Obstet Gynecol 2022; 34:10-14. [PMID: 34967809 DOI: 10.1097/gco.0000000000000760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW This review provides an update on recent developments in cell-based immunotherapy in gynecologic cancers. RECENT FINDINGS Chimeric antigen receptor (CAR) technology has made significant progress allowing now for not only expressing CARs on T-cells, but also on other immune effector cells, such as natural killer cells and macrophages. Cell-based vaccines have started to show promising results in clinical trials. SUMMARY Cell-based immunotherapies in gynecologic cancers continue to evolve with promising clinical efficacy in select patients.
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22
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Ma ES, Wang ZX, Zhu MQ, Zhao J. Immune evasion mechanisms and therapeutic strategies in gastric cancer. World J Gastrointest Oncol 2022; 14:216-229. [PMID: 35116112 PMCID: PMC8790417 DOI: 10.4251/wjgo.v14.i1.216] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/22/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.
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Affiliation(s)
- En-Si Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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23
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Biber G, Sabag B, Raiff A, Ben‐Shmuel A, Puthenveetil A, Benichou JIC, Jubany T, Levy M, Killner S, Barda‐Saad M. Modulation of intrinsic inhibitory checkpoints using nano-carriers to unleash NK cell activity. EMBO Mol Med 2022; 14:e14073. [PMID: 34725941 PMCID: PMC8749471 DOI: 10.15252/emmm.202114073] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 09/22/2021] [Accepted: 09/30/2021] [Indexed: 01/22/2023] Open
Abstract
Natural killer (NK) cells provide a powerful weapon mediating immune defense against viral infections, tumor growth, and metastatic spread. NK cells demonstrate great potential for cancer immunotherapy; they can rapidly and directly kill cancer cells in the absence of MHC-dependent antigen presentation and can initiate a robust immune response in the tumor microenvironment (TME). Nevertheless, current NK cell-based immunotherapies have several drawbacks, such as the requirement for ex vivo expansion of modified NK cells, and low transduction efficiency. Furthermore, to date, no clinical trial has demonstrated a significant benefit for NK-based therapies in patients with advanced solid tumors, mainly due to the suppressive TME. To overcome current obstacles in NK cell-based immunotherapies, we describe here a non-viral lipid nanoparticle-based delivery system that encapsulates small interfering RNAs (siRNAs) to gene silence the key intrinsic inhibitory NK cell molecules, SHP-1, Cbl-b, and c-Cbl. The nanoparticles (NPs) target NK cells in vivo, silence inhibitory checkpoint signaling molecules, and unleash NK cell activity to eliminate tumors. Thus, the novel NP-based system developed here may serve as a powerful tool for future NK cell-based therapeutic approaches.
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Affiliation(s)
- Guy Biber
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Batel Sabag
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Anat Raiff
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Aviad Ben‐Shmuel
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Abhishek Puthenveetil
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Jennifer I C Benichou
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Tammir Jubany
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Moria Levy
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Shiran Killner
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
| | - Mira Barda‐Saad
- The Mina and Everard Goodman Faculty of Life SciencesBar‐Ilan UniversityRamat‐GanIsrael
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24
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Khawar MB, Sun H. CAR-NK Cells: From Natural Basis to Design for Kill. Front Immunol 2022; 12:707542. [PMID: 34970253 PMCID: PMC8712563 DOI: 10.3389/fimmu.2021.707542] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Chimeric antigen receptors (CARs) are fusion proteins with an extracellular antigen recognition domain and numerous intracellular signaling domains that have been genetically modified. CAR-engineered T lymphocyte-based therapies have shown great success against blood cancers; however, potential fatal toxicity, such as in cytokine release syndrome, and high costs are some shortcomings that limit the clinical application of CAR-engineered T lymphocytes and remain to overcome. Natural killer (NK) cells are the focal point of current immunological research owing to their receptors that prove to be promising immunotherapeutic candidates for treating cancer. However, to date, manipulation of NK cells to treat malignancies has been moderately successful. Recent progress in the biology of NK cell receptors has greatly transformed our understanding of how NK cells recognize and kill tumor and infected cells. CAR-NK cells may serve as an alternative candidate for retargeting cancer because of their unique recognition mechanisms, powerful cytotoxic effects especially on cancer cells in both CAR-dependent and CAR-independent manners and clinical safety. Moreover, NK cells can serve as an ‘off-the-shelf product’ because NK cells from allogeneic sources can also be used in immunotherapies owing to their reduced risk of alloreactivity. Although ongoing fundamental research is in the beginning stages, this review provides an overview of recent developments implemented to design CAR constructs to stimulate NK activation and manipulate NK receptors for improving the efficiency of immunotherapy against cancer, summarizes the preclinical and clinical advances of CAR-NK cells against both hematological malignancies and solid tumors and confronts current challenges and obstacles of their applications. In addition, this review provides insights into prospective novel approaches that further enhance the efficiency of CAR-NK therapies and highlights potential questions that require to be addressed in the future.
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Affiliation(s)
- Muhammad Babar Khawar
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research Yangzhou, Yangzhou, China.,Molecular Medicine and Cancer Therapeutics Lab, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan.,Laboratory of Molecular Biology & Genomics, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Haibo Sun
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research Yangzhou, Yangzhou, China
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Inflammaging, an Imbalanced Immune Response That Needs to Be Restored for Cancer Prevention and Treatment in the Elderly. Cells 2021; 10:cells10102562. [PMID: 34685542 PMCID: PMC8533838 DOI: 10.3390/cells10102562] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/03/2021] [Accepted: 09/24/2021] [Indexed: 12/21/2022] Open
Abstract
Nowadays, new advances in society and health have brought an increased life expectancy. However, at the same time, aging comes with complications that impact the development of autoimmunity, neurodegenerative diseases and cancer. These complications affect the quality of life and impact the public health system. Specifically, with aging, a low-grade chronic sterile systemic inflammation with self-reactivity in the absence of acute infection occurs termed inflammaging. Inflammaging is related to an imbalanced immune response that can be either naturally acquired with aging or accelerated due to external triggers. Different molecules, metabolites and inflammatory forms of cell death are highly involved in these processes. Importantly, adoptive cellular immunotherapy is a modality of treatment for cancer patients that administers ex vivo expanded immune cells in the patient. The manipulation of these cells confers them enhanced proinflammatory properties. A general consequence of proinflammatory events is the development of autoimmune diseases and cancer. Herein, we review subsets of immune cells with a pertinent role in inflammaging, relevant proteins involved in these inflammatory events and external triggers that enhance and accelerate these processes. Moreover, we mention relevant preclinical studies that demonstrate associations of chronic inflammation with cancer development.
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Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects. Stem Cell Rev Rep 2021; 17:2081-2106. [PMID: 34472037 PMCID: PMC8410173 DOI: 10.1007/s12015-021-10246-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2021] [Indexed: 12/28/2022]
Abstract
Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative “off-the-shelf” carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.
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Etxebeste-Mitxeltorena M, Del Rincón-Loza I, Martín-Antonio B. Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner. Front Immunol 2021; 12:717850. [PMID: 34447383 PMCID: PMC8382692 DOI: 10.3389/fimmu.2021.717850] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
Adoptive cellular immunotherapy using chimeric antigen receptor (CAR)-modified T cells and Natural Killer (NK) cells are common immune cell sources administered to treat cancer patients. In detail, whereas CAR-T cells induce outstanding responses in a subset of hematological malignancies, responses are much more deficient in solid tumors. Moreover, NK cells have not shown remarkable results up to date. In general, immune cells present high plasticity to change their activity and phenotype depending on the stimuli they receive from molecules secreted in the tumor microenvironment (TME). Consequently, immune cells will also secrete molecules that will shape the activities of other neighboring immune and tumor cells. Specifically, NK cells can polarize to activities as diverse as angiogenic ones instead of their killer activity. In addition, tumor cell phagocytosis by macrophages, which is required to remove dying tumor cells after the attack of NK cells or CAR-T cells, can be avoided in the TME. In addition, chemotherapy or radiotherapy treatments can induce senescence in tumor cells modifying their secretome to a known as “senescence-associated secretory phenotype” (SASP) that will also impact the immune response. Whereas the SASP initially attracts immune cells to eliminate senescent tumor cells, at high numbers of senescent cells, the SASP becomes detrimental, impacting negatively in the immune response. Last, CAR-T cells are an attractive option to overcome these events. Here, we review how molecules secreted in the TME by either tumor cells or even by immune cells impact the anti-tumor activity of surrounding immune cells.
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Affiliation(s)
- Mikel Etxebeste-Mitxeltorena
- Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz, UAM, Madrid, Spain
| | - Inés Del Rincón-Loza
- Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz, UAM, Madrid, Spain
| | - Beatriz Martín-Antonio
- Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz, UAM, Madrid, Spain
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Bachiller M, Perez-Amill L, Battram AM, Carné SC, Najjar A, Verhoeyen E, Juan M, Urbano-Ispizua A, Martin-Antonio B. NK cells enhance CAR-T cell antitumor efficacy by enhancing immune/tumor cells cluster formation and improving CAR-T cell fitness. J Immunother Cancer 2021; 9:jitc-2021-002866. [PMID: 34433634 PMCID: PMC8388291 DOI: 10.1136/jitc-2021-002866] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR)-T cell immunotherapy has modified the concept of treatment in hematological malignancies. In comparison with pediatric patients, where responses are maintained over many years, older patients, such as those with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), present lower persistence of CAR-T cells that might be due to decreased fitness of T cells acquired with aging. Moreover, cord blood derived-NK cells (CB-NKs) and CAR-NK cells derived from CB-NK can be used 'off-the-shelf' as immune cells with antitumor properties for the treatment of cancer patients. However, to date, clinical studies have only demonstrated the safety of these therapies but not optimal efficacy. To confront the shortcomings of each therapy, we devised a novel approach consisting of simultaneous (CAR-)NK cell and CAR-T cell administration. In this setting, NK cells demonstrate an important immunoregulation of T cells that could be exploited to enhance the efficacy of CAR-T cells. METHODS A combinatorial treatment based on either CAR-T and CAR-NK cells or CB-NK and CAR-T cells in two models of NHL and MM was performed. Antitumor efficacy was analyzed in vitro and in vivo, and parameters related to early activation, exhaustion and senescence of T cells were analyzed. RESULTS We show that CAR-NK cells derived from CB-NK are only effective at high doses (high E:T ratio) and that their activity rapidly decreases over time in comparison with CAR-T cells. In comparison and to exploit the potential of 'off-the-shelf' CB-NK, we demonstrate that a low number of CB-NK in the CAR-T cell product promotes an early activation of CAR-T cells and their migration to MM cells leading to enhanced anti-MM efficacy. Moreover, cytokines related to CRS development were not increased, and importantly, CB-NK enhanced the fitness of both CARpos and CARneg T cells, promoting lower levels of exhaustion and senescence. CONCLUSION This study demonstrates a relevant immunoregulatory role of CB-NK collaborating with CAR-T cells to enhance their antitumor activity. A novel and different approach to consider in CAR-T cell immunotherapy studies is presented here with the goal to enhance the efficacy of the treatment.
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Affiliation(s)
- Mireia Bachiller
- Department of Hematology, Hospital Clinic, IDIBAPS, Barcelona, Spain
| | | | | | | | - Amer Najjar
- Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Els Verhoeyen
- CIRI, Université de Lyon, INSERM U1111, ENS de Lyon, Université Lyon 1, Lyon, France.,Université Côte d'Azur, INSERM, Nice, France
| | - Manel Juan
- Department of Immunology, Hospital Clinic de Barcelona (HCB), Platforms of Immunoterapy IDIBAPS HSJD-HCB and BST-HCB, Barcelona, Spain.,Department of Medicine, University of Barcelona, Barcelona, Catalunya, Spain
| | - Alvaro Urbano-Ispizua
- Department of Hematology. University of Barcelona, IDIBAPS, Barcelona, Spain.,Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | - Beatriz Martin-Antonio
- Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz, Madrid, Spain
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Marofi F, Saleh MM, Rahman HS, Suksatan W, Al-Gazally ME, Abdelbasset WK, Thangavelu L, Yumashev AV, Hassanzadeh A, Yazdanifar M, Motavalli R, Pathak Y, Naimi A, Baradaran B, Nikoo M, Khiavi FM. CAR-engineered NK cells; a promising therapeutic option for treatment of hematological malignancies. Stem Cell Res Ther 2021; 12:374. [PMID: 34215336 PMCID: PMC8252313 DOI: 10.1186/s13287-021-02462-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022] Open
Abstract
Adoptive cell therapy has received a great deal of interest in the treatment of advanced cancers that are resistant to traditional therapy. The tremendous success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells in the treatment of cancer, especially hematological cancers, has exposed CAR's potential. However, the toxicity and significant limitations of CAR-T cell immunotherapy prompted research into other immune cells as potential candidates for CAR engineering. NK cells are a major component of the innate immune system, especially for tumor immunosurveillance. They have a higher propensity for immunotherapy in hematologic malignancies because they can detect and eliminate cancerous cells more effectively. In comparison to CAR-T cells, CAR-NK cells can be prepared from allogeneic donors and are safer with a lower chance of cytokine release syndrome and graft-versus-host disease, as well as being a more efficient antitumor activity with high efficiency for off-the-shelf production. Moreover, CAR-NK cells may be modified to target various antigens while also increasing their expansion and survival in vivo. Extensive preclinical research has shown that NK cells can be effectively engineered to express CARs with substantial cytotoxic activity against both hematological and solid tumors, establishing evidence for potential clinical trials of CAR-NK cells. In this review, we discuss recent advances in CAR-NK cell engineering in a variety of hematological malignancies, as well as the main challenges that influence the outcomes of CAR-NK cell-based tumor immunotherapies.
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Affiliation(s)
- Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Science, University of Anbar, Ramadi, Iraq
| | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Chaq-Chaq Qularaise, Sulaimaniyah, Iraq
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, 10210 Thailand
| | | | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | | | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA USA
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yashwant Pathak
- Professor and Associate Dean for Faculty Affairs, Taneja College of Pharmacy, University of South Florida, Tampa, FL USA
- Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | - Adel Naimi
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Behzad Baradaran
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Abstract
ABSTRACT Success from checkpoint blockade and adoptive cell therapy has brought a new hope in cancer immunotherapy. Adoptive cell therapy involves the isolation of immune cells, ex vivo activation and/or expansion, and reinfusion into the patients, and their effect can be dramatically increased by the incorporation of chimeric antigen receptors specific to molecules expressed on tumor cells. Chimeric antigen receptor T cells have shown exciting results in the treatment of liquid malignancies; nevertheless, they suffer from limitations including severe adverse effects such as cytokine release syndrome and neurotoxicity seen in patients as well as a potential for causing graft-versus-host disease in an allogeneic setting. It is thus imperial to explore innate immune cells including natural killer cells, macrophages, natural killer T cells, and γδ T cells. Here, we provide a broad overview of the major innate immune cells and their potential for adoptive cell therapy and chimeric antigen receptor engineering.
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31
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Yilmaz A, Cui H, Caligiuri MA, Yu J. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy. J Hematol Oncol 2020; 13:168. [PMID: 33287875 PMCID: PMC7720606 DOI: 10.1186/s13045-020-00998-9] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
Natural killer (NK) cells are a critical component of the innate immune system. Chimeric antigen receptors (CARs) re-direct NK cells toward tumor cells carrying corresponding antigens, creating major opportunities in the fight against cancer. CAR NK cells have the potential for use as universal CAR cells without the need for human leukocyte antigen matching or prior exposure to tumor-associated antigens. Exciting data from recent clinical trials have renewed interest in the field of cancer immunotherapy due to the potential of CAR NK cells in the production of "off-the-shelf" anti-cancer immunotherapeutic products. Here, we provide an up-to-date comprehensive overview of the recent advancements in key areas of CAR NK cell research and identify under-investigated research areas. We summarize improvements in CAR design and structure, advantages and disadvantages of using CAR NK cells as an alternative to CAR T cell therapy, and list sources to obtain NK cells. In addition, we provide a list of tumor-associated antigens targeted by CAR NK cells and detail challenges in expanding and transducing NK cells for CAR production. We additionally discuss barriers to effective treatment and suggest solutions to improve CAR NK cell function, proliferation, persistence, therapeutic effectiveness, and safety in solid and liquid tumors.
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Affiliation(s)
- Ahmet Yilmaz
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Hanwei Cui
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB, Bldg. 158, 3rd Floor, Room 3017, Los Angeles, CA, 91010, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Department of Immuno-Oncology, City of Hope Beckman Research Institute, Los Angeles, CA, 91010, USA
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, Los Angeles, CA, 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E. Duarte Road, KCRB, Bldg. 158, 3rd Floor, Room 3017, Los Angeles, CA, 91010, USA.
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- Department of Immuno-Oncology, City of Hope Beckman Research Institute, Los Angeles, CA, 91010, USA.
- City of Hope Comprehensive Cancer Center and Beckman Research Institute, Los Angeles, CA, 91010, USA.
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Bachiller M, Battram AM, Perez-Amill L, Martín-Antonio B. Natural Killer Cells in Immunotherapy: Are We Nearly There? Cancers (Basel) 2020; 12:E3139. [PMID: 33120910 PMCID: PMC7694052 DOI: 10.3390/cancers12113139] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/24/2020] [Indexed: 12/17/2022] Open
Abstract
Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.
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Affiliation(s)
| | | | | | - Beatriz Martín-Antonio
- Department of Hematology, Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain; (M.B.); (A.M.B.); (L.P.-A.)
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33
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Battram AM, Bachiller M, Martín-Antonio B. Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword. Int J Mol Sci 2020; 21:ijms21124346. [PMID: 32570952 PMCID: PMC7352478 DOI: 10.3390/ijms21124346] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.
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Affiliation(s)
- Anthony M. Battram
- Department of Hematology, Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain; (A.M.B.); (M.B.)
| | - Mireia Bachiller
- Department of Hematology, Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain; (A.M.B.); (M.B.)
| | - Beatriz Martín-Antonio
- Department of Hematology, Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain; (A.M.B.); (M.B.)
- Department of Hematology, Hospital Clinic, IDIBAPS/Josep Carreras Leukaemia Research Institute, Carrer Rosselló 149-153, 08036 Barcelona, Spain
- Correspondence: ; Tel.: +34-93-227-45-28; Fax: +34-93-312-94-07
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Hoogstad-van Evert JS, Bekkers R, Ottevanger N, Jansen JH, Massuger L, Dolstra H. Harnessing natural killer cells for the treatment of ovarian cancer. Gynecol Oncol 2020; 157:810-816. [PMID: 32268953 DOI: 10.1016/j.ygyno.2020.03.020] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 03/15/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Adoptive cellular immunotherapy could be an interesting new treatment option for ovarian carcinoma (OC), as research has demonstrated that OC is an immunogenic disease. In particular, natural killer (NK) cells have attracted attention due to their ability to kill tumor cells without prior sensitization. The therapeutic value of allogeneic NK cells has been first observed in hematological cancers and is increasingly being explored in solid tumors. METHODS To substantiate the rationale for NK cell therapy in OC we performed a literature search in the Pubmed database and in the international trial register clinicaltrials.gov with attention for the effect of OC on NK cell function, the effect of current treatment on NK cell biology and the evidence on the therapeutic value of NK cell therapy against OC. RESULTS In six clinical trials only 31 OC patients have been reported that received NK cell adoptive transfer. The majority of patients reached stable disease after NK cell therapy, with a mild pattern of side effects. In patients who received repeated infusions, more complete responses are described. All reported studies investigated the intravenous infusion of NK cells. Whereas the studies that are currently recruiting, investigate intraperitoneal infusion of allogeneic NK cells. CONCLUSION In this review the pre-clinical evidence and current trials on NK cell immunotherapy in OC patients are summarized. Furthermore, challenges that have to be overcome for NK cell adoptive therapy to have a significant impact on disease outcome are discussed.
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Affiliation(s)
- Janneke S Hoogstad-van Evert
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Obstetrics and Gynecology, Amphia Hospital, Breda, the Netherlands.
| | - Ruud Bekkers
- Department of Obstetrics and Gynecology, Catharina Ziekenhuis, Eindhoven, the Netherlands; GROW school for oncology and developmental biology, Maastricht University Medical Centre, the Netherlands
| | - Nelleke Ottevanger
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Joop H Jansen
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Leon Massuger
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Harry Dolstra
- Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands
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35
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Shin MH, Kim J, Lim SA, Kim J, Kim SJ, Lee KM. NK Cell-Based Immunotherapies in Cancer. Immune Netw 2020; 20:e14. [PMID: 32395366 PMCID: PMC7192832 DOI: 10.4110/in.2020.20.e14] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 03/01/2020] [Accepted: 03/01/2020] [Indexed: 12/11/2022] Open
Abstract
With the development of technologies that can transform immune cells into therapeutic modalities, immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. NK cells are components of the innate immune system that act as key regulators and exhibit a potent tumor cytolytic function. Unlike T cells, NK cells exhibit tumor cytotoxicity by recognizing non-self, without deliberate immunization or activation. Currently, researchers have developed various approaches to improve the number and anti-tumor function of NK cells. These approaches include the use of cytokines and Abs to stimulate the efficacy of NK cell function, adoptive transfer of autologous or allogeneic ex vivo expanded NK cells, establishment of homogeneous NK cell lines using the NK cells of patients with cancer or healthy donors, derivation of NK cells from induced pluripotent stem cells (iPSCs), and modification of NK cells with cutting-edge genetic engineering technologies to generate chimeric Ag receptor (CAR)-NK cells. Such NK cell-based immunotherapies are currently reported as being promising anti-tumor strategies that have shown enhanced functional specificity in several clinical trials investigating malignant tumors. Here, we summarize the recent advances in NK cell-based cancer immunotherapies that have focused on providing improved function through the use of the latest genetic engineering technologies. We also discuss the different types of NK cells developed for cancer immunotherapy and present the clinical trials being conducted to test their safety and efficacy.
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Affiliation(s)
- Min Hwa Shin
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Junghee Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Siyoung A Lim
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Jungwon Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
| | - Seong-Jin Kim
- Precision Medicine Research Center, Advanced Institutes of Convergence Technology, Seoul National University, Suwon 16229, Korea
| | - Kyung-Mi Lee
- Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seoul 02841, Korea
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36
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Yang C, Li Y, Yang Y, Chen Z. Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell. J Immunol Res 2020; 2020:8459496. [PMID: 32411806 PMCID: PMC7201677 DOI: 10.1155/2020/8459496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 11/24/2019] [Accepted: 12/04/2019] [Indexed: 12/14/2022] Open
Abstract
NK cells are lymphocytes with antitumor properties and can directly lyse tumor cells in a non-MHC-restricted manner. However, the tumor microenvironment affects the immune function of NK cells, which leads to immune evasion. This may be related to the pathogenesis of some diseases. Therefore, great efforts have been made to improve the immunotherapy effect of natural killer cells. NK cells from different sources can meet different clinical needs, in order to minimize the inhibition of NK cells and maximize the response potential of NK cells, for example, modification of NK cells can increase the number of NK cells in tumor target area, change the direction of NK cells, and improve their targeting ability to malignant cells. Checkpoint blocking is also a promising strategy for NK cells to kill tumor cells. Combination therapy is another strategy for improving antitumor ability, especially in combination with oncolytic viruses and nanomaterials. In this paper, the mechanisms affecting the activity of NK cells were reviewed, and the therapeutic potential of different basic NK cell strategies in tumor therapy was focused on. The main strategies for improving the immune function of NK cells were described, and some new strategies were proposed.
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Affiliation(s)
- Chaopin Yang
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
- Experimental Center, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510176, China
| | - Yue Li
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
- Experimental Center, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510176, China
| | - Yaozhang Yang
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
- Experimental Center, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510176, China
| | - Zhiyi Chen
- Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
- Experimental Center, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510176, China
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37
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Schanoski AS, Le TT, Kaiserman D, Rowe C, Prow NA, Barboza DD, Santos CA, Zanotto PMA, Magalhães KG, Aurelio L, Muller D, Young P, Zhao P, Bird PI, Suhrbier A. Granzyme A in Chikungunya and Other Arboviral Infections. Front Immunol 2020; 10:3083. [PMID: 31993061 PMCID: PMC6971054 DOI: 10.3389/fimmu.2019.03083] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/17/2019] [Indexed: 12/23/2022] Open
Abstract
Granzyme A (GzmA) is secreted by cytotoxic lymphocytes and has traditionally been viewed as a mediator of cell death. However, a growing body of data suggests the physiological role of GzmA is promotion of inflammation. Here, we show that GzmA is significantly elevated in the sera of chikungunya virus (CHIKV) patients and that GzmA levels correlated with viral loads and disease scores in these patients. Serum GzmA levels were also elevated in CHIKV mouse models, with NK cells the likely source. Infection of mice deficient in type I interferon responses with CHIKV, Zika virus, or dengue virus resulted in high levels of circulating GzmA. We also show that subcutaneous injection of enzymically active recombinant mouse GzmA was able to mediate inflammation, both locally at the injection site as well as at a distant site. Protease activated receptors (PARs) may represent targets for GzmA, and we show that treatment with PAR antagonist ameliorated GzmA- and CHIKV-mediated inflammation.
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Affiliation(s)
| | - Thuy T Le
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Dion Kaiserman
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Caitlin Rowe
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Natalie A Prow
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Australian Infectious Disease Research Centre, University of Queensland, Brisbane, QLD, Australia
| | - Diego D Barboza
- Bacteriology Laboratory, Butantan Institute, São Paulo, Brazil
| | - Cliomar A Santos
- Health Foundation Parreiras Horta, Central Laboratory of Public Health, State Secretary for Health, Aracajú, Brazil
| | - Paolo M A Zanotto
- Laboratory of Molecular Evolution and Bioinformatics, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil
| | - Kelly G Magalhães
- Laboratory of Immunology and Inflammation, University of Brasilia, Brasilia, Brazil
| | - Luigi Aurelio
- Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - David Muller
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
| | - Paul Young
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia
| | - Peishen Zhao
- Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Phillip I Bird
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Australian Infectious Disease Research Centre, University of Queensland, Brisbane, QLD, Australia
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38
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Martín-Antonio B, Suñe G, Najjar A, Perez-Amill L, Antoñana-Vildosola A, Castella M, León S, Velasco-de Andrés M, Lozano F, Lozano E, Bueno C, Estanyol JM, Muñoz-Pinedo C, Robinson SN, Urbano-Ispizua A. Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor. J Immunother Cancer 2019; 7:259. [PMID: 31619273 PMCID: PMC6794915 DOI: 10.1186/s40425-019-0739-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 09/12/2019] [Indexed: 12/25/2022] Open
Abstract
Background Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. Methods TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. Results We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. Conclusion This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies.
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Affiliation(s)
- B Martín-Antonio
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain. .,Josep Carreras Leukaemia Research Institute, Carrer Rosselló 149-153, 08036, Barcelona, Spain.
| | - G Suñe
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain.,Josep Carreras Leukaemia Research Institute, Carrer Rosselló 149-153, 08036, Barcelona, Spain
| | - A Najjar
- Department of Pediatrics - Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - L Perez-Amill
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain
| | - A Antoñana-Vildosola
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain
| | - M Castella
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain
| | - S León
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain
| | - M Velasco-de Andrés
- Immunoreceptors of the Innate and Adaptive System Group, IDIBAPS, Barcelona, Spain
| | - F Lozano
- Immunoreceptors of the Innate and Adaptive System Group, IDIBAPS, Barcelona, Spain.,Department of Immunology, Hospital Clinic of Barcelona, Barcelona, Spain.,Department of Biomedical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
| | - E Lozano
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain
| | - C Bueno
- Josep Carreras Leukemia Research Institute and Cell Therapy Program of the School of Medicine, University of Barcelona, Barcelona, Spain
| | - J M Estanyol
- Proteomic department, University of Barcelona, Barcelona, Spain
| | - C Muñoz-Pinedo
- Cell Death Regulation Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - S N Robinson
- Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - A Urbano-Ispizua
- Department of Hematology, Hospital Clinic, IDIBAPS, Carrer Rosselló 149-153, 08036, Barcelona, Spain.,Josep Carreras Leukaemia Research Institute, Carrer Rosselló 149-153, 08036, Barcelona, Spain.,Department of Hematology, University of Barcelona, Barcelona, Spain
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Jaiswal SR, Chakrabarti S. Natural killer cell-based immunotherapy with CTLA4Ig-primed donor lymphocytes following haploidentical transplantation. Immunotherapy 2019; 11:1221-1230. [DOI: 10.2217/imt-2019-0037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
NK cell-based immunotherapy is one of the more exciting propositions in the field of cellular therapy for hematological malignancies. Current protocols are largely based on expanded and activated NK cells which are used both with and without allogeneic transplantation. Based on our recent findings, we discuss the concept of CTLA4Ig-primed donor lymphocyte infusions following haploidentical transplantation as an effective tool to garner NK cell-mediated antitumor effect with abrogation of T cell-mediated alloreactivity. This approach might widen the possibility of immunotherapy following haploidentical transplantation without increase in graft-versus-host disease. Further studies would be needed to establish the veracity of this concept with better understanding of the antitumor effect via this pathway. Future studies would decide if CTLA4Ig might be used to augment NK-cell activation in vitro as well.
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Affiliation(s)
- Sarita Rani Jaiswal
- Cellular Therapy & Immunology, Manashi Chakrabarti Foundation, Kolkata
- Department of Blood & Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital & Research Centre, New Delhi, India
| | - Suparno Chakrabarti
- Cellular Therapy & Immunology, Manashi Chakrabarti Foundation, Kolkata
- Department of Blood & Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital & Research Centre, New Delhi, India
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40
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Sahin U, Beksac M. Natural Killer Cell-Mediated Cellular Therapy of Hematological Malignancies. Clin Hematol Int 2019; 1:134-141. [PMID: 34595423 PMCID: PMC8432367 DOI: 10.2991/chi.d.190623.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 06/20/2019] [Indexed: 11/09/2022] Open
Abstract
Our understanding on the mechanisms of graft versus tumor/leukemia (GvT/GvL) and graft versus host (GvH) effects has tremendously evolved within the past decades. During the search for a mechanism that augments GvT/GvL without increasing GvH effects, natural killer (NK) cells have clearly attracted attention. Current approaches of NK cell immunotherapy for hematological malignancies involve using methods for in vivo potentiation of NK cell proliferation and activity; adoptive transfer of NK cells from autologous and allogeneic sources [cord blood mononuclear cells, peripheral blood mononuclear cells, CD34+ stem cells] and NK cell lines; and genetic modification of NK cells. Several cytokines, including interleukin-2 and interleukin-15 take part in the development of NK cells and have been shown to boost NK cell effects both in vivo and ex vivo. Monoclonal antibodies directed towards certain targets, including stimulating CD16, blockade of NK cell receptors, and redirection of cytotoxicity to tumor cells via bi- or tri-specific engagers may promote NK cell function. Despite the relative disappointment with autologous NK cell infusions, the future holds promise in adoptive transfer of allogeneic NK cells and the development of novel cellular therapeutic strategies, such as chimeric antigen receptor-modified NK cell immunotherapy. In this review, we summarize the current status of NK cell-related mechanisms in the therapy of hematologic malignancies, and discuss the future perspectives on adoptive NK cell transfer and other novel cellular immunotherapeutic strategies.
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Affiliation(s)
- Ugur Sahin
- Hematology Unit, Yenimahalle Education and Research Hospital, Yildirim Beyazit University, Ankara, Turkey
| | - Meral Beksac
- Department of Hematology, Faculty of Medicine, Ankara University, Cebeci Hospital, 06220, Ankara, Turkey
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41
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Hu S, Yang J, Shangguan J, Eresen A, Li Y, Ma Q, Yaghmai V, Velichko Y, Hu C, Zhang Z. Natural killer cell-based adoptive transfer immunotherapy for pancreatic ductal adenocarcinoma in a KrasLSL-G12D p53LSL-R172H Pdx1-Cre mouse model. Am J Cancer Res 2019; 9:1757-1765. [PMID: 31497356 PMCID: PMC6726992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 07/19/2019] [Indexed: 06/10/2023] Open
Abstract
Natural killer (NK) cells play a pivotal role in host immunity against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our study aimed to evaluate the antitumor effects of NK cell-based adoptive transfer immunotherapy for PDAC in an orthotopic mouse model. Orthotopic KrasLSL-G12D p53LSL-R172H Pdx1-Cre (KPC) mice were used to evaluate the therapeutic efficacy. Mouse NK cells (LNK cells) (1×106) were intravenously injected to tumor-bearing mice once a week for 3 weeks. MRI measurements (tumor volume and apparent diffusion coefficient (ADC) values) and survival were compared between control and LNK treated tumors. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to determine LNK cells cytotoxicity and IFN-γ level, respectively. LNK cells can produce a higher level of IFN-γ and more effectively lyse PDAC cells compared with spleen NK cells in vitro. LNK-cell adoptive transfer therapy elicited potent in vivo antitumor activity, resulting in delayed tumor growth (P=0.033) in KPC mice. The ADC values at the last timepoint ((0.94±0.06)×10-3 mm2/s) were significantly higher than that at first timepoint ((0.75±0.04)×10-3 mm2/s) in treated tumors (P<0.001). ADC values were significantly different between control group and treated tumors at the last time point ((0.75±0.09)×10-3 mm2/s vs (0.94±0.06)×10-3 mm2/s, P=0.004) in KPC mice. Our data demonstrate the potential of NK cell-based adoptive transfer immunotherapy for PDAC treatment.
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Affiliation(s)
- Su Hu
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
- Department of Radiology, The First Affiliated Hospital of Soochow UniversitySuzhou, Jiangsu, China
| | - Jia Yang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Junjie Shangguan
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Aydin Eresen
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Yu Li
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
- Department of General Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, China
| | - Quanhong Ma
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Vahid Yaghmai
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityChicago, IL, USA
| | - Yuri Velichko
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityChicago, IL, USA
| | - Chunhong Hu
- Department of Radiology, The First Affiliated Hospital of Soochow UniversitySuzhou, Jiangsu, China
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityChicago, IL, USA
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Choi YH, Lim EJ, Kim SW, Moon YW, Park KS, An HJ. IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. J Immunother Cancer 2019; 7:168. [PMID: 31277710 PMCID: PMC6612093 DOI: 10.1186/s40425-019-0652-7] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 06/21/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells are an emerging new tool for cancer immunotherapy. To develop NK cell therapeutics from peripheral blood mononuclear cells (PBMCs) of healthy donors, substantial expansion of primary NK cells is necessary because of the very low number of these cells in peripheral blood. In this study, we aimed to investigate the effect of various cytokine alone or combinations, in expanded NK cells and to analyze the synergetic effect of cytokine combinations. METHODS Human NK cells were isolated from healthy donor PBMC. Purified NK cells were stimulated with single cytokines or combinations of IL-2, IL-15, IL-18, and IL-27. The expanded NK cells were characterized by flow cytometry, cytotoxicity assay, calcein AM assay and Western blot. RESULTS We investigated the synergistic effects of each cytokine, namely, IL-2, IL-15, IL-18, and IL-27, on human NK cells isolated from PBMCs of healthy donors and cultured for 21 days. We identified that IL-15/IL-18/IL-27-mediated activation of NK cells most potently increased NK cell proliferation, cytotoxicity, and IFN-ɣ secretion compared with the activation observed with other treatments, including IL-2, IL-15, and IL-15/IL-18. Additionally, the expression of DNAM-1, NKG2D, CD69, and natural cytotoxicity receptors (NCRs; NKp30 and NKp44) increased on day 21 compared to that on day 0, demonstrating the activation of NK cells. In vitro, expanded NK cells were highly cytotoxic against cancer cells, displaying increased perforin and granzyme B accumulation. CONCLUSIONS Taken together, these results indicated that IL-27 can synergize on NK cell expansion and activation with IL-15 and IL-18. In addition, we described an improved culture method for ex vivo expansion of human NK cells with IL-15/IL-18/IL-27 stimulation and characterized the response of NK cells to this stimulation.
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Affiliation(s)
- Yeon Ho Choi
- Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea
| | - Eun Jin Lim
- Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea
| | - Se Wha Kim
- Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea.,Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea
| | - Yong Wha Moon
- Department of Medical Oncology, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea
| | - Kyung Soon Park
- Department of Biomedical Science, CHA University, Sungnam, Gyeonggi-do, Republic of Korea
| | - Hee-Jung An
- Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea. .,Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Gyeonggi-do, Republic of Korea.
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Geng X, Li M, Cui B, Lu C, Liu X, Zhang P, Liu B, Ma C, Shen Y, Lu Z. CD4+CD25+Foxp3+ regulatory T cells suppress NKG2D-mediated NK cell cytotoxicity in peripheral blood. Medicine (Baltimore) 2019; 98:e15722. [PMID: 31145286 PMCID: PMC6708973 DOI: 10.1097/md.0000000000015722] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Studies have shown that CD4CD25Foxp3Treg cells suppress NKG2D expression on NK cells via a cell contact-dependent mechanism and increased TGF-β and IL-10 production in some cancer models. We herein aimed to explore whether CD4CD25Foxp3Tregs suppress NKG2D-mediated NK cell cytotoxicity in peripheral blood and elucidate the exact mechanism underlying this phenomenon. METHODS To explore the function of NKG2D, NK cell cultures were treated with an NKG2D-blocking antibody to block these receptors. Additionally, TGF-β- and IL-10-blocking antibodies were added to NK and CD4CD25Foxp3Treg cell cocultures to evaluate whether the latter cells suppress NKG2D expression of NK cells via increasing the production of TGF-β and IL-10. The expression of NKG2D on NK cells was detected by 3-color flow cytometry, and NK cell activity was assessed by 3 assays: a nonradioactive cytotoxicity assay, an ELISA measuring IFN-γ production and a flow cytometry assay to evaluate CD107a expression. RESULTS Blocking NKG2D decreased NK cell cytotoxicity, IFN-γ production and CD107a expression. Moreover, blocking TGF-β and IL-10 substantially increased the NKG2D expression in NK and CD4CD25Foxp3Treg cell cocultures. Similarly, blocking TGF-β and IL-10 enhanced NK cell cytotoxicity, IFN-γ production and CD107a expression; Transwell insert assays also revealed increased IFN-γ production and CD107a and NKG2D expression. CONCLUSION CD4CD25Foxp3Tregs suppress NKG2D-mediated NK cell cytotoxicity in peripheral blood via a cell contact-dependent mechanism and increased TGF-β and IL-10 production.
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Affiliation(s)
- Xu Geng
- Department of Clinical Laboratory
| | - Ming Li
- Department of Clinical Laboratory
| | - Bin Cui
- Department of Central Laboratory
| | - Chao Lu
- Department of Clinical Laboratory
| | | | - Peng Zhang
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, PR China
| | - Bin Liu
- Department of Central Laboratory
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Natural Killer Immunotherapy for Minimal Residual Disease Eradication Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia. Int J Mol Sci 2019; 20:ijms20092057. [PMID: 31027331 PMCID: PMC6539946 DOI: 10.3390/ijms20092057] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 04/21/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022] Open
Abstract
The most common cause of death in patients with acute myeloid leukemia (AML) who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) is AML relapse. Therefore, additive therapies post allo-HSCT have significant potential to prevent relapse. Natural killer (NK)-cell-based immunotherapies can be incorporated into the therapeutic armamentarium for the eradication of AML cells post allo-HSCT. In recent studies, NK cell-based immunotherapies, the use of adoptive NK cells, NK cells in combination with cytokines, immune checkpoint inhibitors, bispecific and trispecific killer cell engagers, and chimeric antigen receptor-engineered NK cells have all shown antitumor activity in AML patients. In this review, we will discuss the current strategies with these NK cell-based immunotherapies as possible therapies to cure AML patients post allo-HSCT. Additionally, we will discuss various means of immune escape in order to further understand the mechanism of NK cell-based immunotherapies against AML.
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45
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El Assal R, Abou‐Elkacem L, Tocchio A, Pasley S, Matosevic S, Kaplan DL, Zylberberg C, Demirci U. Bioinspired Preservation of Natural Killer Cells for Cancer Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1802045. [PMID: 30937270 PMCID: PMC6425501 DOI: 10.1002/advs.201802045] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Indexed: 05/11/2023]
Abstract
The ability to cryopreserve natural killer (NK) cells has a significant potential in modern cancer immunotherapy. Current cryopreservation protocols cause deterioration in NK cell viability and functionality. This work reports the preservation of human cytokine-activated NK cell viability and function following cryopreservation using a cocktail of biocompatible bioinspired cryoprotectants (i.e., dextran and carboxylated ε-poly-L-lysine). Results demonstrate that the recovered NK cells after cryopreservation and rewarming maintain their viability immediately after thawing at a comparable level to control (dimethyl sulfoxide-based cryopreservation). Although, their viability drops in the first day in culture compared to controls, the cells grow back to a comparable level to controls after 1 week in culture. In addition, the anti-tumor functional activity of recovered NK cells demonstrates higher cytotoxic potency against leukemia cells compared to control. This approach presents a new direction for NK cell preservation, focusing on function and potentially enabling storage and distribution for cancer immunotherapy.
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Affiliation(s)
- Rami El Assal
- Bio‐Acoustic‐MEMS in Medicine (BAMM) LaboratoriesCanary Center at Stanford for Cancer Early DetectionDepartment of RadiologyStanford University School of MedicinePalo AltoCA94304USA
| | - Lotfi Abou‐Elkacem
- Molecular Imaging Program at Stanford (MIPS)Department of RadiologyStanford University School of MedicinePalo AltoCA94304USA
| | - Alessandro Tocchio
- Bio‐Acoustic‐MEMS in Medicine (BAMM) LaboratoriesCanary Center at Stanford for Cancer Early DetectionDepartment of RadiologyStanford University School of MedicinePalo AltoCA94304USA
| | | | - Sandro Matosevic
- Department of Industrial and Physical PharmacyCollege of PharmacyPurdue UniversityWest LafayetteIN47907USA
| | - David L. Kaplan
- Department of Biomedical EngineeringTufts University School of EngineeringMedfordMA02155USA
| | | | - Utkan Demirci
- Bio‐Acoustic‐MEMS in Medicine (BAMM) LaboratoriesCanary Center at Stanford for Cancer Early DetectionDepartment of RadiologyStanford University School of MedicinePalo AltoCA94304USA
- Department of Electrical Engineering (by courtesy)Stanford University School of EngineeringPalo AltoCA94304USA
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46
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Eisenberg V, Hoogi S, Shamul A, Barliya T, Cohen CJ. T-cells "à la CAR-T(e)" - Genetically engineering T-cell response against cancer. Adv Drug Deliv Rev 2019; 141:23-40. [PMID: 30653988 DOI: 10.1016/j.addr.2019.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 01/01/2019] [Accepted: 01/09/2019] [Indexed: 02/06/2023]
Abstract
The last decade will be remembered as the dawn of the immunotherapy era during which we have witnessed the approval by regulatory agencies of genetically engineered CAR T-cells and of checkpoint inhibitors for cancer treatment. Understandably, T-lymphocytes represent the essential player in these approaches. These cells can mediate impressive tumor regression in terminally-ill cancer patients. Moreover, they are amenable to genetic engineering to improve their function and specificity. In the present review, we will give an overview of the most recent developments in the field of T-cell genetic engineering including TCR-gene transfer and CAR T-cells strategies. We will also elaborate on the development of other types of genetic modifications to enhance their anti-tumor immune response such as the use of co-stimulatory chimeric receptors (CCRs) and unconventional CARs built on non-antibody molecules. Finally, we will discuss recent advances in genome editing and synthetic biology applied to T-cell engineering and comment on the next challenges ahead.
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Du Y, Wei Y. Therapeutic Potential of Natural Killer Cells in Gastric Cancer. Front Immunol 2019; 9:3095. [PMID: 30719024 PMCID: PMC6348255 DOI: 10.3389/fimmu.2018.03095] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Accepted: 12/13/2018] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers, with a high incidence of cancer death. Despite various therapeutic approaches, the cures and prognosis of advanced GC remain poor. Natural killer (NK) cells, which are known as important lymphocytes in innate immunity, play vital roles in suppressing GC initiation, progression, and metastases. A wide range of clinical settings shows that increasing the number of NK cells or improving NK cell antitumor activity is promising in GC patients. NK cell adoptive therapy (especially expanded NK cells) is a safe and well-tolerated method, which can enhance NK cell cytotoxicity against GC. Meanwhile, cytokines, immunomodulatory drugs, immune checkpoint blockades, antibodies, vaccines, and gene therapy have been found to directly or indirectly activate NK cells to improve their killing activity toward GC. In this review, we summarize recent advancements in the relationship between NK cells and GC and point out all the innovative strategies that can enhance NK cells' function to inhibit the growth of GC.
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Affiliation(s)
- Yu Du
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yongchang Wei
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China
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48
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Natural Killer Cells and Current Applications of Chimeric Antigen Receptor-Modified NK-92 Cells in Tumor Immunotherapy. Int J Mol Sci 2019; 20:ijms20020317. [PMID: 30646574 PMCID: PMC6358726 DOI: 10.3390/ijms20020317] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 12/22/2022] Open
Abstract
Natural killer (NK) cells are innate immune cells that can be activated rapidly to target abnormal and virus-infected cells without prior sensitization. With significant advancements in cell biology technologies, many NK cell lines have been established. Among these cell lines, NK-92 cells are not only the most widely used but have also been approved for clinical applications. Additionally, chimeric antigen receptor-modified NK-92 cells (CAR-NK-92 cells) have shown strong antitumor effects. In this review, we summarize established human NK cell lines and their biological characteristics, and highlight the applications of NK-92 cells and CAR-NK-92 cells in tumor immunotherapy.
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Bernareggi D, Pouyanfard S, Kaufman DS. Development of innate immune cells from human pluripotent stem cells. Exp Hematol 2019; 71:13-23. [PMID: 30611869 DOI: 10.1016/j.exphem.2018.12.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 12/23/2018] [Accepted: 12/30/2018] [Indexed: 02/07/2023]
Abstract
Mouse and human pluripotent stem cells have been widely used to study the development of the hematopoietic and immune systems. Although not all cells can be derived with the same efficiency, immune cells such as natural killer (NK) cells and macrophages can be easily produced from PSCs to enable development of new cell-based therapies. NK cells and macrophages are part of the innate immune system, the first line of defense against malignancies and infectious disease. Human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-derived NK cells can be produced at a clinical scale suitable for translation into clinical trials. Additionally, PSCs can be genetically modified to produce hESC/iPSC-derived human NK cells with enhanced antitumor activity. These engineered NK cells can express a stabilized version of the high-affinity Fc receptor CD16, chimeric antigen receptors, or other strategies to enable more potent and targeted cellular immunotherapies. Moreover, macrophages can also be routinely and efficiently produced from hESCs and iPSCs as a tool to expand our knowledge of the basic biology of these cells. hESC- and iPSC-derived macrophages can also be employed as a novel approach for cancer immunotherapy, as well as a strategy to repair or regenerate diseased and damaged tissues and organs.
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Affiliation(s)
- Davide Bernareggi
- Department of Medicine, Division of Regenerative Medicine, University of California San Diego, CA
| | - Somayeh Pouyanfard
- Department of Medicine, Division of Regenerative Medicine, University of California San Diego, CA
| | - Dan S Kaufman
- Department of Medicine, Division of Regenerative Medicine, University of California San Diego, CA.
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50
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Mahaweni NM, Ehlers FAI, Bos GMJ, Wieten L. Tuning Natural Killer Cell Anti-multiple Myeloma Reactivity by Targeting Inhibitory Signaling via KIR and NKG2A. Front Immunol 2018; 9:2848. [PMID: 30564241 PMCID: PMC6288976 DOI: 10.3389/fimmu.2018.02848] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 11/19/2018] [Indexed: 12/11/2022] Open
Abstract
Natural killer (NK) cells are attractive candidates for allogeneic cell-based immunotherapy due to their potent antitumor effector function and good safety profile. NK cells express killer immunoglobulin-like receptors (KIRs) and the NKG2A receptor important for NK cells education as well as providing inhibitory signals upon encountering HLA-expressing target cells. Multiple myeloma (MM) is an example of a tumor expressing relatively high levels of HLA molecules. In this review, we discuss the functional relevance of inhibitory KIRs and NKG2A for NK cells anti-MM response and strategies to lower these inhibitory signaling to enhance clinical efficacy of allogeneic NK cells in MM.
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Affiliation(s)
- Niken M Mahaweni
- Division of Hematology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, Netherlands.,GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Tissue Typing Laboratory, Department of Transplantation Immunology, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Femke A I Ehlers
- Division of Hematology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, Netherlands.,GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Tissue Typing Laboratory, Department of Transplantation Immunology, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Gerard M J Bos
- Division of Hematology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, Netherlands.,GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Lotte Wieten
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Tissue Typing Laboratory, Department of Transplantation Immunology, Maastricht University Medical Center+, Maastricht, Netherlands
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