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1
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Huerta-Yepez S, Chen PC, Kaur K, Jain Y, Singh T, Esedebe F, Liao YJ, DiBernardo G, Moatamed NA, Mei A, Malarkannan S, Graeber TG, Memarzadeh S, Jewett A. Supercharged NK cells, unlike primary activated NK cells, effectively target ovarian cancer cells irrespective of MHC-class I expression. BMJ ONCOLOGY 2025; 4:e000618. [PMID: 40196236 PMCID: PMC11973776 DOI: 10.1136/bmjonc-2024-000618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/07/2025] [Indexed: 04/09/2025]
Abstract
Objective To demonstrate the significance of supercharged natural killer (sNK) cells to target aggressive gynecological tumours. Methods and analysis We used cell cultures of peripheral blood-derived mononuclear cells (PBMCs) and purified NK cells alone and in the presence of tumours. MHC-class gene expression assessments of ovarian tumours were performed using gene set enrichment analysis (GSEA). Secretion and expression levels of cytokines in PBMCs and NK cells were determined using ELISA and scRNA seq analysis, respectively. A flow cytometer was used for surface marker analysis. 51Cr and eSight were used to determine the killing activity of NK cells. Results We have observed a significant decrease in the numbers and functions of NK cells in patients with ovarian cancer. GSEA revealed differently expressed genes, decreased differentiation- and immune-related genes, and increased genes for cell cycle analysis in recurrent tumours compared with chemo-naive ovarian tumours. Increased gene expression as well as secretion of interferon-γ and tumour necrosis factor-α and increased avidity in binding to tumour cells by sNK cells was observed. Unlike primary interleukin (IL)-2-activated NK cells, sNK cells effectively lysed OVCAR8 ovarian poorly differentiated cancer stem-like cells (PDCSCs) and well-differentiated OVCAR4 tumours. Primary ovarian tumours with lower MHC-class I expression were highly susceptible to both primary IL-2-activated NK and sNK cells, whereas the well-differentiated tumours with high expression of MHC-class I were only susceptible to sNK cells. Conclusion The use of sNK cells in immunotherapy emerges as a potentially effective strategy to target and eliminate the majority of ovarian tumour clones, thereby providing a potential therapeutic opportunity in preventing the recurrence of the disease.
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Affiliation(s)
- Sara Huerta-Yepez
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Le Conte Ave, Los Angeles, USA
- Oncology Research Unit, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico
| | - Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Le Conte Ave, Los Angeles, USA
| | - Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Le Conte Ave, Los Angeles, USA
| | - Yash Jain
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Le Conte Ave, Los Angeles, USA
| | - Tanya Singh
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, USA
| | - Favour Esedebe
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California, USA
| | - Yi Jou Liao
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California, USA
| | - Gabriella DiBernardo
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, USA
| | - Neda A Moatamed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Ao Mei
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, USA
| | - Subramaniam Malarkannan
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States, Milwaukee, Wisconsin, USA
| | - Thomas G Graeber
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California, USA
- The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
- Crump Institute for Molecular Imaging, Medical laboratory in Los Angeles, Los Angeles, California, USA
| | - Sanaz Memarzadeh
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
- The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
- Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA
- The VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Le Conte Ave, Los Angeles, USA
- The Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
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Rishabh K, Matosevic S. The diversity of natural killer cell functional and phenotypic states in cancer. Cancer Metastasis Rev 2025; 44:26. [PMID: 39853430 DOI: 10.1007/s10555-025-10242-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/08/2025] [Indexed: 01/26/2025]
Abstract
The role of natural killer (NK) cells as immune effectors is well established, as is their utility as immunotherapeutic agents against various cancers. However, NK cells' anti-cancer roles are suppressed in cancer patients by various immunomodulatory mechanisms which alter these cells' identity, function, and potential for immunosurveillance. This manifests in abnormal NK cell responses accompanied by changes in phenotypic or genotypic identity, giving rise to specific NK cell subsets that are either hypofunctional or, more broadly, defective in their responses. Anergy, senescence, and exhaustion are some of the terms that have been used to define and characterize these NK cell functional states. These responses vary not only with cancer type but also NK cell location within tissues. Collectively, these phenomena suggest a highly plastic nature of NK cell biology in tumors. In this review, we present and discuss a summary of these functionally distinct states and provide an overview of how NK cells behave at different locations within the context of cancer.
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Affiliation(s)
- Kumar Rishabh
- Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA
| | - Sandro Matosevic
- Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, USA.
- Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
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3
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Kaur K, Jewett A. Role of Natural Killer Cells as Cell-Based Immunotherapy in Oral Tumor Eradication and Differentiation Both In Vivo and In Vitro. Crit Rev Immunol 2024; 44:87-98. [PMID: 38618731 DOI: 10.1615/critrevimmunol.2024052389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Despite advancements in the field of cancer therapeutics, the five-year survival rate remains low in oral cancer patients. Therefore, the effective therapeutics are needed against oral cancer. Also, several studies including ours, have shown severely suppressed function and number of NK cells in oral cancer patients. In this review, we discuss the approach to inhibit the tumor growth and metastasis by direct killing or NK cell-mediated tumor differentiation. This review also provides an overview on supercharging NK cells using osteoclasts and probiotic bacteria, and their efficacy as cancer immunotherapeutic in humanized-BLT mice.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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4
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Senjor E, Pirro M, Švajger U, Prunk M, Sabotič J, Jewett A, Hensbergen PJ, Perišić Nanut M, Kos J. Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells. Cell Mol Life Sci 2023; 81:8. [PMID: 38092995 PMCID: PMC10719177 DOI: 10.1007/s00018-023-05041-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 10/13/2023] [Accepted: 11/06/2023] [Indexed: 12/17/2023]
Abstract
Cystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients.
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Affiliation(s)
- Emanuela Senjor
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000, Ljubljana, Slovenia
| | - Martina Pirro
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Urban Švajger
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000, Ljubljana, Slovenia
- Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia
| | - Mateja Prunk
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Jerica Sabotič
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California Los Angeles, Los Angeles, USA
- The Jonsson Comprehensive Cancer Center, Los Angeles, USA
| | - Paul J Hensbergen
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Janko Kos
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000, Ljubljana, Slovenia.
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5
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Bai X, Cao R, Wu D, Zhang H, Yang F, Wang L. Dental Pulp Stem Cells for Bone Tissue Engineering: A Literature Review. Stem Cells Int 2023; 2023:7357179. [PMID: 37868704 PMCID: PMC10586346 DOI: 10.1155/2023/7357179] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 06/03/2023] [Accepted: 09/19/2023] [Indexed: 10/24/2023] Open
Abstract
Bone tissue engineering (BTE) is a promising approach for repairing and regenerating damaged bone tissue, using stem cells and scaffold structures. Among various stem cell sources, dental pulp stem cells (DPSCs) have emerged as a potential candidate due to their multipotential capabilities, ability to undergo osteogenic differentiation, low immunogenicity, and ease of isolation. This article reviews the biological characteristics of DPSCs, their potential for BTE, and the underlying transcription factors and signaling pathways involved in osteogenic differentiation; it also highlights the application of DPSCs in inducing scaffold tissues for bone regeneration and summarizes animal and clinical studies conducted in this field. This review demonstrates the potential of DPSC-based BTE for effective bone repair and regeneration, with implications for clinical translation.
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Affiliation(s)
- Xiaolei Bai
- Department of Stomatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310018, Zhejiang, China
| | - Ruijue Cao
- Department of Stomatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310018, Zhejiang, China
| | - Danni Wu
- Center for Plastic & Reconstructive Surgery, Department of Stomatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310018, Zhejiang, China
| | - Huicong Zhang
- Center for Plastic & Reconstructive Surgery, Department of Stomatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310018, Zhejiang, China
| | - Fan Yang
- Center for Plastic & Reconstructive Surgery, Department of Stomatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310018, Zhejiang, China
| | - Linhong Wang
- Center for Plastic & Reconstructive Surgery, Department of Stomatology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310018, Zhejiang, China
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Fu X, Liu Z, Wang Y. Advances in the Study of Immunosuppressive Mechanisms in Sepsis. J Inflamm Res 2023; 16:3967-3981. [PMID: 37706064 PMCID: PMC10497210 DOI: 10.2147/jir.s426007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/29/2023] [Indexed: 09/15/2023] Open
Abstract
Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient's chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.
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Affiliation(s)
- Xuzhe Fu
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Zhi Liu
- Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Yu Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
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7
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Maya J. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2023; 24:11937. [PMID: 37569313 PMCID: PMC10418326 DOI: 10.3390/ijms241511937] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.
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Affiliation(s)
- Jessica Maya
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA
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8
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Pawlowski KD, Duffy JT, Tiwari A, Zannikou M, Balyasnikova IV. Bi-Specific Killer Cell Engager Enhances NK Cell Activity against Interleukin-13 Receptor Alpha-2 Positive Gliomas. Cells 2023; 12:1716. [PMID: 37443750 PMCID: PMC10340194 DOI: 10.3390/cells12131716] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
Glioblastoma (GBM) is a lethal brain tumor with limited therapeutic options. Bi-specific killer cell engagers (BiKEs) are novel immunotherapies designed to engage natural killer (NK) cells against cancer. We designed a BiKE molecule consisting of a single-domain CD16 antibody, an interleukin-15 linker, and a single-chain variable antibody against the glioma-associated antigen interleukin 13 receptor alpha 2 (IL13Rα2). Recombinant BiKE protein was expressed in HEK cells and purified. Flow cytometric analysis of co-cultures of peripheral blood-derived NK cells with GBM6 and GBM39 patient-derived xenograft lines revealed significantly increased activation of NK cells (CD25+CD69+) and increased glioma cell killing following BiKE treatment compared to controls (n = 4, p < 0.01). Glioma cell killing was also confirmed via immunofluorescence staining for cleaved caspase-3 (p < 0.05). In vivo, intracranial delivery of NK cells with BiKE extended median survival in mice bearing GBM6 (p < 0.01) and GBM12 (p < 0.01) tumors compared to controls. Finally, histological analysis of brain tissues revealed a higher frequency of peritumoral NK cells in mice treated with BiKE than with NK cells alone (p < 0.05). In conclusion, we demonstrate that a BiKE generated in a mammalian expression system is functional in augmenting NK cell targeting of IL13Rα2-positive gliomas.
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Affiliation(s)
- Kristen D. Pawlowski
- Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA
- Rush Medical College, Rush University Medical Center, Chicago, IL 60612, USA
| | - Joseph T. Duffy
- Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA
| | - Arushi Tiwari
- Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA
| | - Markella Zannikou
- Department of Neurological Surgery, Northwestern University, Chicago, IL 60611, USA
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9
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Kaur K, Chen PC, Ko MW, Mei A, Senjor E, Malarkannan S, Kos J, Jewett A. Sequential therapy with supercharged NK cells with either chemotherapy drug cisplatin or anti-PD-1 antibody decreases the tumor size and significantly enhances the NK function in Hu-BLT mice. Front Immunol 2023; 14:1132807. [PMID: 37197660 PMCID: PMC10183580 DOI: 10.3389/fimmu.2023.1132807] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/31/2023] [Indexed: 05/19/2023] Open
Abstract
Introduction and methods In this study we report that sequential treatment of supercharged NK (sNK) cells with either chemotherapeutic drugs or check-point inhibitors eliminate both poorly differentiated and well differentiated tumors in-vivo in humanized-BLT mice. Background and results sNK cells were found to be a unique population of activated NK cells with genetic, proteomic, and functional attributes that are very different from primary untreated or IL-2 treated NK cells. Furthermore, NK-supernatant differentiated or well-differentiated oral or pancreatic tumor cell lines are not susceptible to IL-2 activated primary NK cell-mediated cytotoxicity; however, they are greatly killed by the CDDP and paclitaxel in in-vitro assays. Injection of one dose of sNK cells at 1 million cells per mouse to aggressive CSC-like/poorly differentiated oral tumor bearing mice, followed by an injection of CDDP, inhibited tumor weight and growth, and increased IFN-γ secretion as well as NK cell-mediated cytotoxicity substantially in bone marrow, spleen and peripheral blood derived immune cells. Similarly, the use of check point inhibitor anti-PD-1 antibody increased IFN-γ secretion and NK cell-mediated cytotoxicity, and decreased the tumor burden in-vivo, and tumor growth of resected minimal residual tumors from hu-BLT mice when used sequentially with sNK cells. The addition of anti-PDL1 antibody to poorly differentiated MP2, NK-differentiated MP2 or well-differentiated PL-12 pancreatic tumors had different effects on tumor cells depending on the differentiation status of the tumor cells, since differentiated tumors expressed PD-L1 and were susceptible to NK cell mediated ADCC, whereas poorly differentiated OSCSCs or MP2 did not express PD-L1 and were killed directly by the NK cells. Conclusions Therefore, the ability to target combinatorially clones of tumors with NK cells and chemotherapeutic drugs or NK cells with checkpoint inhibitors at different stages of tumor differentiation may be crucial for successful eradication and cure of cancer. Furthermore, the success of check point inhibitor PD-L1 may relate to the levels of expression on tumor cells.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA, United States
| | - Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA, United States
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA, United States
| | - Ao Mei
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI, United States
| | - Emanuela Senjor
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA, United States
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Subramaniam Malarkannan
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI, United States
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Janko Kos
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA, United States
- The Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA) School of Dentistry and Medicine, Los Angeles, CA, United States
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10
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Xiao R, Ma Y, Li H, Li X, Sun Z, Qi Q, Yin P, Yang F, Qiu M. Lung adenocarcinoma manifesting as subsolid nodule potentially represents tumour in the equilibrium phase of immunoediting. Immunology 2023; 168:290-301. [PMID: 35503794 DOI: 10.1111/imm.13489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/09/2022] [Indexed: 01/17/2023] Open
Abstract
Lung adenocarcinomas manifesting as subsolid nodules (SSN-LUADs) possess distinct dormant behaviour. This study was designed to compare the immune landscapes of normal lungs (nLungs), SSN-LUADs and LUADs manifesting as solid nodules (SN-LUADs) so as to better understand the status of anti-tumour immunity in SSN-LUADs. Mass cytometry by time-of-flight analysis was performed on 299, 570 single cells from nLung, SSN-LUAD and SN-LUAD tissues. The immune cells were identified by phenotype, and the percentages of different immune cell subclusters were compared between SSN-LUADs, SN-LUADs and nLungs. Elevated percentage of CD8+ T cells were identified in SSN-LUADs compared with in nLungs and SN-LUADs. Elevated CD56bright NK cells and decreased CD56dim NK cells were identified in both SSN-LUADs and SN-LUADs compared with in nLungs. The immune landscape of SSN-LUAD fits the theory of equilibrium phase of immunoediting, thus functional adaptive anti-tumour immunity but impaired innate anti-tumour immunity potentially contributes to the maintaining of its dormant behaviour.
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Affiliation(s)
- Rongxin Xiao
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Yi Ma
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Hao Li
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Xiao Li
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Zewen Sun
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Qingyi Qi
- Department of Radiology, Peking University People's Hospital, Beijing, China
| | - Ping Yin
- Department of Radiology, Peking University People's Hospital, Beijing, China
| | - Fan Yang
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
| | - Mantang Qiu
- Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
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11
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Kaur K, Sun Y, Kanayama K, Morinaga K, Hokugo A, Nishimura I, Jewett A. Augmentation of IFN-γ by bone marrow derived immune cells in the presence of severe suppression of IFN-γ in gingivae induced by zoledronic acid and denosumab in Hu-BLT mice model of ONJ. Front Endocrinol (Lausanne) 2023; 14:1111627. [PMID: 36742414 PMCID: PMC9895394 DOI: 10.3389/fendo.2023.1111627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 01/03/2023] [Indexed: 01/22/2023] Open
Abstract
Introduction The potential mechanisms governing drug induced osteonecrosis of the jaw (ONJ) is not well understood, and is one of the objectives of this study. Thus, we tested the release of IFN-γ within different immune compartments including bone marrow and gingivae upon treatment with zoledronic acid (ZOL) and denosumab which are known to induce ONJ in susceptible individuals. Methods We used humanized-BLT mouse model for the in-vivo studies reported in this paper. To determine the effects of zoledronic acid and denosumab on IFN-γ secretion and NK cell-mediated cytotoxicity; peripheral blood, bone marrow, spleen and gingiva were obtained after the injection of ZOL and denosumab in mice. Results Percentages of B cells are much higher in wild-type mice whereas the proportions of immune subsets in humans and reconstituted hu-BLT peripheral-blood are similar. Therefore, hu-BLT mice are preferable model to study human disease, in particular, immune-pathologies induced by ZOL and denosumab. Both agents resulted in a severe suppression of IFN-γ in the gingiva, whereas they heightened the release of IFN-γ and NK cell-mediated cytotoxicity by the BM-derived immune cells. ZOL increased the IFN-γ secretion by the spleen and peripheral blood immune cells, whereas denosumab decreased the release IFN-γ by these cells significantly. Discussion ZOL and denosumab may likely suppress IFN-γ secretion in gingiva through different mechanisms. In addition, to the suppression of IFN-γ secretion, denosumab mediated effect could in part be due to the decrease in the bone resorptive function of osteoclasts due to the induction of antibody dependent cellular cytotoxicity and lysis of osteoclasts, whereas ZOL is able to mediate cell death of osteoclasts directly. Suppression of IFN-gamma in gingiva is largely responsible for the inhibition of immune cell function, leading to dysregulated osteoblastic and osteoclastic activities. Restoration of IFN-gamma in the local microenvironment may result in establishment of homeostatic balance in the gingiva and prevention of osteonecrosis of jaw.
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Affiliation(s)
- Kawaljit Kaur
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Oral Biology and Medicine, University of California School of Dentistry, Los Angeles, CA, United States
| | - Yujie Sun
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Advanced Prosthodontics, University of California School of Dentistry, Los Angeles, CA, United States
| | - Keiichi Kanayama
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Advanced Prosthodontics, University of California School of Dentistry, Los Angeles, CA, United States
- Department of Periodontology, Asahi University School of Dentistry, Gifu, Japan
| | - Kenzo Morinaga
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Advanced Prosthodontics, University of California School of Dentistry, Los Angeles, CA, United States
- Department of Oral Rehabilitation, Fukuoka Dental College, Fukuoka, Japan
| | - Akishige Hokugo
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Plastic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Ichiro Nishimura
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Oral Biology and Medicine, University of California School of Dentistry, Los Angeles, CA, United States
- Division of Advanced Prosthodontics, University of California School of Dentistry, Los Angeles, CA, United States
| | - Anahid Jewett
- Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, United States
- Division of Oral Biology and Medicine, University of California School of Dentistry, Los Angeles, CA, United States
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Kaur K, Chen PC, Ko MW, Mei A, Huerta-Yepez S, Maharaj D, Malarkannan S, Jewett A. Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis. Crit Rev Immunol 2023; 43:1-11. [PMID: 37522557 DOI: 10.1615/critrevimmunol.2023047235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Ao Mei
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Sara Huerta-Yepez
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA 90095, USA
| | - Dipnarine Maharaj
- South Florida Bone Marrow Stem Cell Transplant Institute, DBA Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437
| | - Subramaniam Malarkannan
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee WI 53226; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Department of Pediatrics, Medical College of Wisconsin, Milwaukee WI
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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Kaur K, Jewett A. Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers. Crit Rev Immunol 2023; 43:13-25. [PMID: 37938193 DOI: 10.1615/critrevimmunol.2023050618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
In this paper, we review a number of in vitro and in vivo studies regarding the efficacy of supercharged NK (sNK) cell therapy in elimination or treatment of cancer. We have performed studies using six different types of cancer models of oral, pancreatic, glioblastoma, melanoma, hepatic and ovarian cancers using hu-BLT mice. Our in vitro studies demonstrated that primary NK cells preferentially target cancer stem-like cells (CSCs)/poorly differentiated tumors whereas sNK cells target both CSCs/poorly-differentiated and well-differentiated tumors significantly higher than primary activated NK cells. Our in vivo studies in humanized-BLT mice showed that sNK cells alone or in combination with other cancer therapeutics prevented tumor growth and metastasis. In addition, sNK cells were able to increase IFN-γ secretion and cytotoxic function by the immune cells in bone marrow, spleen, gingiva, pancreas and peripheral blood. Furthermore, sNK cells were able to increase the expansion and function of CD8+ T cells both in in vitro and in vivo studies. Overall, our studies demonstrated that sNK cells alone or in combination with other cancer therapeutics were not only effective against eliminating aggressive cancers, but were also able to increase the expansion and function of CD8+ T cells to further target cancer cells, providing a successful approach to eradicate and cure cancer.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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Kaur K, Jewett A. Differences in Tumor Growth and Differentiation in NSG and Humanized-BLT Mice; Analysis of Human vs. Humanized-BLT-Derived NK Expansion and Functions. Cancers (Basel) 2022; 15:112. [PMID: 36612108 PMCID: PMC9817973 DOI: 10.3390/cancers15010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/17/2022] [Accepted: 12/17/2022] [Indexed: 12/28/2022] Open
Abstract
There is significant interest and debate regarding the best mouse model of human disease, since studies in wild-type mice may not always recapitulate human diseases. The NSG mouse model has been one of the most commonly used mouse models to study cancer; however, this mouse model, even though it has several advantages in regard to the ease of tumor implantation and financial feasibility, does not represent human disease due to the immunodeficient nature of this model. In this study, we performed oral and pancreatic tumor studies in NSG and hu-BLT mice and found several distinguishing features that make hu-BLT model more suitable for studying human cancer. In addition, we compared the immune function of humans to hu-BLT mice to understand the differences and similarities of the models. Oral and pancreatic cancer stem cells were implanted in NSG and hu-BLT mice. Both tumors grew robustly in NSG mice and killed them within a short period of time. On the contrary, unlike NSG mice, tumor-bearing hu-BLT mice survived longer, grew smaller tumors, and the grown tumors exhibited lower rates of expansion, with a higher surface expression of MHC-class I and lower NK cell-mediated cytotoxicity that was previously shown to have more of a differentiated phenotype. Although the peripheral blood of hu-BLT mice in comparison to that of humans had lower percentages of NK cells and cytotoxic function, it mediated a higher secretion of IFN-γ, likely contributing to the differentiation of the tumor cells and subsequent decrease in the tumor size in the hu-BLT mice in comparison to the NSG mice. Spleen-derived hu-BLT mouse NK cells were able to expand in the presence of autologous osteoclasts and substantially increase both cytotoxicity and secretion of IFN-γ, similar to those seen in peripheral blood-derived human NK cells, indicating that NK cells from hu-BLT mice are capable of expansion and functional activation when activating signals are given. Thus, the many similarities between human and hu-BLT mouse immune systems make this mouse model more appropriate to study human cancer. In particular, it is well-suited for studies of allogeneic NK cell-based immunotherapy in cancer treatment. The advantages and challenges of hu-BLT mice in cancer studies are also discussed in this report.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, University of California, School of Dentistry and Medicine, Los Angeles, CA 90095, USA
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California, School of Dentistry and Medicine, Los Angeles, CA 90095, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, University of California, School of Dentistry and Medicine, Los Angeles, CA 90095, USA
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California, School of Dentistry and Medicine, Los Angeles, CA 90095, USA
- The Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA
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Kaur K, Ko MW, Chen F, Jewett A. Defective NK cell expansion, cytotoxicity, and lack of ability to differentiate tumors from a pancreatic cancer patient in a long term follow-up: implication in the progression of cancer. Cancer Immunol Immunother 2022; 71:1033-1047. [PMID: 34559307 DOI: 10.1007/s00262-021-03044-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/23/2021] [Indexed: 11/25/2022]
Abstract
The majority of the previous reports on NK cells use cross-sectional studies to establish the status of patient NK cell function, however such studies fail to evaluate the immune status of the patients on a continuous basis from the disease-free stage to progression of cancer. In this study, we performed a prospective study of the immune function by continuously monitoring the NK numbers, expansion and function of a pancreatic cancer patient from 1/6/2016 to 2/14/2019. The results indicated that at initial stages of the disease where no overt disease was identified, the patient had consistently higher percentages of NK and B cells and lower percentages of CD3 + T cells in the peripheral blood. The percentages of CD14 + monocytes were similar at the initial stages of the disease, and at the later stages of the disease, it increased and remained higher in the patient when compared to those from healthy donors. The numbers of expanded NK cells and the cytotoxic function, as well as secretion of IFN-γ from primary and osteoclast expanded patient NK cells remained consistently low throughout the years of follow up. Similarly, the majority of cytokines in patient's serum remained lower with the exception of IL-6 which was higher. The IFN-γ secreted from the patients' NK cells had much lower ability to differentiate the poorly differentiated oral tumors as assessed by their lack of ability to upregulate differentiation antigens. Overall, before any evidence of overt disease, patient NK cells exhibited significant dysfunction. Intervention at the stage of no disease or minimal disease may be important for the prevention of pancreatic cancer progression.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Franklin Chen
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA, USA.
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave., Los Angeles, CA, 90095, USA.
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Ko MW, Kaur K, Safaei T, Chen W, Sutanto C, Wong P, Jewett A. Defective Patient NK Function Is Reversed by AJ2 Probiotic Bacteria or Addition of Allogeneic Healthy Monocytes. Cells 2022; 11:cells11040697. [PMID: 35203349 PMCID: PMC8870139 DOI: 10.3390/cells11040697] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
In this paper, we present the role of autologous and allogeneic monocytes from healthy individuals and those of the cancer patients, with a number of distinct cancers, in activating the function of natural killer (NK) cells, in particular, in induction of IFN-γ secretion by the NK cells and the functional capability of secreted IFN-γ in driving differentiation of the tumor cells. In addition, we compared the roles of CD16 signaling as well as sonicated probiotic bacteria AJ2 (sAJ2)-mediated induction and function of IFN-γ-mediated differentiation in tumor cells. We found that monocytes from cancer patients had lower capability to induce functional IFN-γ secretion by the autologous CD16 mAb-treated NK cells in comparison to those from healthy individuals. In addition, when patient monocytes were cultured with NK cells from healthy individuals, they had lower capability to induce functional IFN-γ secretion by the NK cells when compared to those from autologous monocyte/NK cultures from healthy individuals. Activation by sAJ2 or addition of monocytes from healthy individuals to patient NK cells increased the secretion of functional IFN-γ by the NK cells and elevated its functional capability to differentiate tumors. Monocytes from cancer patients were found to express lower CD16 receptors, providing a potential mechanism for their lack of ability to trigger secretion of functional IFN-γ. In addition to in vitro studies, we also conducted in vivo studies in which cancer patients were given oral supplementation of AJ2 and the function of NK cells were studied. Oral ingestion of AJ2 improved the secretion of IFN-γ by patient derived NK cells and resulted in the better functioning of NK cells in cancer patients. Thus, our studies indicate that for successful NK cell immunotherapy, not only the defect in NK cells but also those in monocytes should be corrected. In this regard, AJ2 probiotic bacteria may serve to provide a potential adjunct treatment strategy.
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Affiliation(s)
- Meng-Wei Ko
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Kawaljit Kaur
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Tahmineh Safaei
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Wuyang Chen
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Christine Sutanto
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Paul Wong
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
| | - Anahid Jewett
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA 90095, USA; (M.-W.K.); (K.K.); (T.S.); (W.C.); (C.S.); (P.W.)
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
- Correspondence: ; Tel.: +1-310-206-3970; Fax: +1-301-794-7109
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Song J, Zhou H, Gu D, Xu Y. Hepatocellular Carcinoma Differentiation: Research Progress in Mechanism and Treatment. Front Oncol 2022; 11:790358. [PMID: 35096588 PMCID: PMC8790246 DOI: 10.3389/fonc.2021.790358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Although progress has been made in diagnosis and treatment, morbidity and mortality continue to rise. Chronic liver disease and liver cirrhosis are still the most important risk factors for liver cancer. Although there are many treatments, it can only be cured by orthotopic liver transplantation (OLT) or surgical resection. And the worse the degree of differentiation, the worse the prognosis of patients with liver cancer. Then it can be considered that restoring a better state of differentiation may improve the prognosis. The differentiation treatment of liver cancer is to reverse the dedifferentiation process of hepatocytes to liver cancer cells by means of drugs, improve the differentiation state of the tumor, and restore the normal liver characteristics, so as to improve the prognosis. Understanding the mechanism of dedifferentiation of liver cancer can provide ideas for drug design. Liver enrichment of transcription factors, imbalance of signal pathway and changes of tumor microenvironment can promote the occurrence and development of liver cancer, and restoring its normal level can inhibit the malignant behavior of tumor. At present, some drugs have been proved to be effective, but more clinical data are needed to support the effectiveness and reliability of drugs. The differentiation treatment of liver cancer is expected to become an important part of the treatment of liver cancer in the future.
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Affiliation(s)
- Jianning Song
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Guangzhou Medical University, Shenzhen, China
| | - Hongzhong Zhou
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Dayong Gu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China
| | - Yong Xu
- Department of Clinical Laboratory, Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.,Guangzhou Medical University, Shenzhen, China
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Shokouhifar A, Firouzi J, Nouri M, Sarab GA, Ebrahimi M. NK cell upraise in the dark world of cancer stem cells. Cancer Cell Int 2021; 21:682. [PMID: 34923966 PMCID: PMC8684645 DOI: 10.1186/s12935-021-02400-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/08/2021] [Indexed: 12/29/2022] Open
Abstract
One of the obstacles in treating different cancers, especially solid tumors, is cancer stem cells (CSCs) with their ability in resistance to chemo/radio therapy. The efforts for finding advanced treatments to overcome these cells have led to the emergence of advanced immune cell-based therapy (AICBT). Today, NK cells have become the center of attention since they have been proved to show an appropriate cytotoxicity against different cancer types as well as the capability of detecting and killing CSCs. Attempts for reaching an off-the-shelf source of NK cells have been made and resulted in the emergence of chimeric antigen receptor natural killer cells (CAR-NK cells). The CAR technology has then been used for generating more cytotoxic and efficient NK cells, which has increased the hope for cancer treatment. Since utilizing this advanced technology to target CSCs have been published in few studies, the present study has focused on discussing the characteristics of CSCs, which are detected and targeted by NK cells, the advantages and restrictions of using CAR-NK cells in CSCs treatment and the probable challenges in this process.
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Affiliation(s)
- Alireza Shokouhifar
- Department of Molecular Medicine, Genomic Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, 16635-148, Tehran, Iran
| | - Javad Firouzi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, 16635-148, Tehran, Iran.,Department of Tissue Engineering & Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Nouri
- R&D Department, Royan Stem Cell Technology Co., Tehran, Iran
| | - Gholamreza Anani Sarab
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, 16635-148, Tehran, Iran. .,Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, 14155-4364, Tehran, Iran.
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Kaur K, Vaziri S, Romero-Reyes M, Paranjpe A, Jewett A. Phenotypic and Functional Alterations of Immune Effectors in Periodontitis; A Multifactorial and Complex Oral Disease. J Clin Med 2021; 10:jcm10040875. [PMID: 33672708 PMCID: PMC7924323 DOI: 10.3390/jcm10040875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 11/16/2022] Open
Abstract
Survival and function of immune subsets in the oral blood, peripheral blood and gingival tissues of patients with periodontal disease and healthy controls were assessed. NK and CD8 + T cells within the oral blood mononuclear cells (OBMCs) expressed significantly higher levels of CD69 in patients with periodontal disease compared to those from healthy controls. Similarly, TNF-α release was higher from oral blood of patients with periodontal disease when compared to healthy controls. Increased activation induced cell death of peripheral blood mononuclear cells (PBMCs) but not OBMCs from patients with periodontal disease was observed when compared to those from healthy individuals. Unlike those from healthy individuals, OBMC-derived supernatants from periodontitis patients exhibited decreased ability to induce secretion of IFN-γ by allogeneic healthy PBMCs treated with IL-2, while they triggered significant levels of TNF-α, IL-1β and IL-6 by untreated PBMCs. Interaction of PBMCs, or NK cells with intact or NFκB knock down oral epithelial cells in the presence of a periodontal pathogen, F. nucleatum, significantly induced a number of pro-inflammatory cytokines including IFN-γ. These studies indicated that the relative numbers of immune subsets obtained from peripheral blood may not represent the composition of the immune cells in the oral environment, and that orally-derived immune effectors may differ in survival and function from those of peripheral blood.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA 90095, USA; (K.K.); (S.V.)
| | - Shahram Vaziri
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA 90095, USA; (K.K.); (S.V.)
| | - Marcela Romero-Reyes
- Department of Neural and Pain Sciences, University of Maryland, Baltimore, MD 21201, USA;
| | - Avina Paranjpe
- Department of Endodontics, University of Washington, Seattle, DC 98195, USA;
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, School of Dentistry and Medicine, Los Angeles, CA 90095, USA; (K.K.); (S.V.)
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
- Correspondence: ; Tel.: +1-310-206-3970; Fax: +1-310-794-7109
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ADCC against MICA/B Is Mediated against Differentiated Oral and Pancreatic and Not Stem-Like/Poorly Differentiated Tumors by the NK Cells; Loss in Cancer Patients due to Down-Modulation of CD16 Receptor. Cancers (Basel) 2021; 13:cancers13020239. [PMID: 33440654 PMCID: PMC7826810 DOI: 10.3390/cancers13020239] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 01/05/2023] Open
Abstract
Tumor cells are known to upregulate major histocompatibility complex-class I chain related proteins A and B (MICA/B) expression under stress conditions or due to radiation exposure. However, it is not clear whether there are specific stages of cellular maturation in which these ligands are upregulated or whether the natural killer (NK) cells differentially target these tumors in direct cytotoxicity or antibody-dependent cell cytotoxicity (ADCC). We used freshly isolated primary and osteoclast (OCs)-expanded NK cells to determine the degree of direct cytotoxicity or of ADCC using anti-MICA/B monoclonal antibodies (mAbs) against oral stem-like/poorly-differentiated oral squamous cancer stem cells (OSCSCs) and Mia PaCa-2 (MP2) pancreatic tumors as well as their well-differentiated counterparts: namely, oral squamous carcinoma cells (OSCCs) and pancreatic PL12 tumors. By using phenotypic and functional analysis, we demonstrated that OSCSCs and MP2 tumors were primary targets of direct cytotoxicity by freshly isolated NK cells and not by ADCC mediated by anti-MICA/B mAbs, which was likely due to the lower surface expression of MICA/B. However, the inverse was seen when their MICA/B-expressing differentiated counterparts, OSCCs and PL12 tumors, were used in direct cytotoxicity and ADCC, in which there was lower direct cytotoxicity but higher ADCC mediated by the NK cells. Differentiation of the OSCSCs and MP2 tumors by NK cell-supernatants abolished the direct killing of these tumors by the NK cells while enhancing NK cell-mediated ADCC due to the increased expression of MICA/B on the surface of these tumors. We further report that both direct killing and ADCC against MICA/B expressing tumors were significantly diminished by cancer patients' NK cells. Surprisingly, OC-expanded NK cells, unlike primary interleukin-2 (IL-2) activated NK cells, were found to kill OSCCs and PL12 tumors, and under these conditions, we did not observe significant ADCC using anti-MICA/B mAbs, even though the tumors expressed a higher surface expression of MICA/B. In addition, differentiated tumor cells also expressed higher levels of surface epidermal growth factor receptor (EGFR) and programmed death-ligand 1(PDL1) and were more susceptible to NK cell-mediated ADCC in the presence of anti-EGFR and anti-PDL1 mAbs compared to their stem-like/poorly differentiated counterparts. Overall, these results suggested the possibility of CD16 receptors mediating both direct cytotoxicity and ADCC, resulting in the competitive use of these receptors in either direct killing or ADCC, depending on the differentiation status of tumor cells and the stage of maturation and activation of NK cells.
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21
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Ostapchuk YO, Perfilyeva YV, Kali A, Tleulieva R, Yurikova OY, Stanbekova GE, Karalnik BV, Belyaev NN. Fc Receptor is Involved in Nk Cell Functional Anergy Induced by Miapaca2 Tumor Cell Line. Immunol Invest 2020; 51:138-153. [PMID: 32865068 DOI: 10.1080/08820139.2020.1813757] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Impaired NK cytotoxicity has been linked to poor cancer prognosis, but its mechanisms are not clearly established. Increasing data demonstrate that NK cells lose cytotoxicity after interaction with NK cell-sensitive tumor cells. In this paper, we provide evidence that the human adenocarcinoma cell line MiaPaCa2 and TNFα and TGFβ-treated MiaPaCa2 cultures (MiaPaCa2-TT) induced functional anergy of NK cells via FGL2 protein. MiaPaCa2-TT cultures decreased expression of IFNγ, CD107a, DNAM-1, and stimulated expression of PD1 by NK cells, as well as inhibited their cytotoxic activity in a greater manner compared to the parental culture. More importantly, we found that co-cultivation with anergized NK cells decreased expression of IFNγ and CD107a by naïve NK cells, which supports the hypothesis of NK cell functional anergy transmission. The obtained results suggest a mechanism by which tumor cells may inhibit cytotoxic functions of tumor-infiltrating and circulating NK cells in cancer. ABBREVIATIONS CFSE: Carboxyfluorescein diacetate succinimidyl ester; CSCs: Cancer stem cells; FGL2: Fibrinogen-like protein 2; mAbs: Monoclonal antibodies; MiaPaCa2: Human adenocarcinoma cell line; MiaPaCa2-ТТ: Adenocarcinoma cell line MiaPaCa2 cells stimulated with TNFα and TGFβ-1; PI: Propidium iodide; TGFβ: Transforming growth factor beta; TME: Tumor microenvironment; TNFα: Tumor necrosis factor alfa.
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Affiliation(s)
- Yekaterina O Ostapchuk
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Yuliya V Perfilyeva
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Aikyn Kali
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan.,Biomedical Research Center, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Raikhan Tleulieva
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Oxana Yu Yurikova
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Gulshan E Stanbekova
- Laboratory of Protein and Nucleic Acids, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Boris V Karalnik
- Scientific Center for Hygiene and Epidemiology named after Kh. Zhumatov, Natioanl Public Health Center, Almaty, Kazakhstan
| | - Nikolai N Belyaev
- Department of New Technologies, Saint-Petersburg Pasteur Institute, Saint-Petersburg, Russia
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22
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Alhabbab RY. Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells. Front Genet 2020; 11:312. [PMID: 32391048 PMCID: PMC7188929 DOI: 10.3389/fgene.2020.00312] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/16/2020] [Indexed: 12/11/2022] Open
Abstract
The term cancer stem cell (CSC) starts 25 years ago with the evidence that CSC is a subpopulation of tumor cells that have renewal ability and can differentiate into several distinct linages. Therefore, CSCs play crucial role in the initiation and the maintenance of cancer. Moreover, it has been proposed throughout several studies that CSCs are behind the failure of the conventional chemo-/radiotherapy as well as cancer recurrence due to their ability to resist the therapy and their ability to re-regenerate. Thus, the need for targeted therapy to eliminate CSCs is crucial; for that reason, chimeric antigen receptor (CAR) T cells has currently been in use with high rate of success in leukemia and, to some degree, in patients with solid tumors. This review outlines the most common CSC populations and their common markers, in particular CD133, CD90, EpCAM, CD44, ALDH, and EGFRVIII, the interaction between CSCs and the immune system, CAR T cell genetic engineering and signaling, CAR T cells in targeting CSCs, and the barriers in using CAR T cells as immunotherapy to treat solid cancers.
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Affiliation(s)
- Rowa Y. Alhabbab
- Division of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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23
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Judge SJ, Murphy WJ, Canter RJ. Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence. Front Cell Infect Microbiol 2020; 10:49. [PMID: 32117816 PMCID: PMC7031155 DOI: 10.3389/fcimb.2020.00049] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/24/2020] [Indexed: 12/24/2022] Open
Abstract
There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules associated with immune exhaustion (such as PD-1, but also TIGIT, and LAG-3) has led to a revolution in oncology with dramatic benefits in a growing list of solid and hematologic malignancies. Given this success in reinvigorating exhausted T cells and the related anti-tumor effects, there are increasing efforts to apply immune checkpoint blockade to other exhausted immune cells beyond T cells. One approach involves the reinvigoration of “exhausted” NK cells, a non-T, non-B lymphoid cell of the innate immune system. However, in contrast to the more well-defined and established molecular, genetic, and immunophenotypic characteristics of T cell exhaustion, a consensus on the defining functional and phenotypic features of NK “exhaustion” is less clear. As is well-known from T cell biology, separate and distinct molecular and cellular processes including senescence, anergy and exhaustion can lead to diminished immune effector function with different implications for immune regulation and recovery. For NK cells, it is unclear if exhaustion, anergy, and senescence entail separate and distinct entities of dysfunction, though all are typically characterized by decreased effector function or proliferation. In this review, we seek to define these distinct spheres of NK cell dysfunction, analyzing how they have been shown to impact NK biology and clinical applications, and ultimately highlight key characteristics in NK cell function, particularly in relation to the role of “exhaustion.”
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Affiliation(s)
- Sean J Judge
- Division of Surgical Oncology, Department of Surgery, University of California, Davis, Sacramento, CA, United States
| | - William J Murphy
- Department of Dermatology, University of California, Davis, Sacramento, CA, United States.,Department of Medicine, University of California, Davis, Sacramento, CA, United States
| | - Robert J Canter
- Division of Surgical Oncology, Department of Surgery, University of California, Davis, Sacramento, CA, United States
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24
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Kaur K, Kozlowska AK, Topchyan P, Ko MW, Ohanian N, Chiang J, Cook J, Maung PO, Park SH, Cacalano N, Fang C, Jewett A. Probiotic-Treated Super-Charged NK Cells Efficiently Clear Poorly Differentiated Pancreatic Tumors in Hu-BLT Mice. Cancers (Basel) 2019; 12:cancers12010063. [PMID: 31878338 PMCID: PMC7017229 DOI: 10.3390/cancers12010063] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 01/01/2023] Open
Abstract
Abstract: Background and Aims: We have previously demonstrated that the stage of differentiation of tumors has profound effect on the function of NK cells, and that stem-like/poorly differentiated tumors were preferentially targeted by the NK cells. Therefore, in this study we determined the role of super-charged NK cells in immune mobilization, lysis, and differentiation of stem-like/undifferentiated tumors implanted in the pancreas of humanized-BLT (hu-BLT) mice fed with or without AJ2 probiotics. The phenotype, growth rate and metastatic potential of pancreatic tumors differentiated by the NK cells (NK-differentiated) or patient derived differentiated or stem-like/undifferentiated pancreatic tumors were investigated. Methods: Pancreatic tumor implantation was performed in NSG and hu-BLT mice. Stage of differentiation of tumors was determined using our published criteria for well-differentiated tumors exhibiting higher surface expression of MHC- class I, CD54, and PD-L1 (B7H1) and lower expression of CD44 receptors. The inverse was seen for poorly-differentiated tumors. Results: Stem-like/undifferentiated pancreatic tumors grew rapidly and formed large tumors and exhibited lower expression of above-mentioned differentiation antigens in the pancreas of NSG and hu-BLT mice. Unlike stem-like/undifferentiated tumors, NK-differentiated MP2 (MiaPaCa-2) tumors or patient-derived differentiated tumors were not able to grow or grew smaller tumors, and were unable to metastasize in NSG or hu-BLT mice, and they were susceptible to chemotherapeutic drugs. Stem-like/undifferentiated pancreatic tumors implanted in the pancreas of hu-BLT mice and injected with super-charged NK cells formed much smaller tumors, proliferated less, and exhibited differentiated phenotype. When differentiation of stem-like tumors by the NK cells was prevented by the addition of antibodies to IFN-γ and TNF-α, tumors grew rapidly and metastasized, and they remained resistant to chemotherapeutic drugs. Greater numbers of immune cells infiltrated the tumors of NK-injected and AJ2-probiotic bacteria-fed mice. Moreover, increased IFN-γ secretion in the presence of decreased IL-6 was seen in tumors resected and cultured from NK-injected and AJ2 fed mice. Tumor-induced decreases in NK cytotoxicity and IFN-γ secretion were restored/increased within PBMCs, spleen, and bone marrow when mice received NK cells and were fed with AJ2. Conclusion: NK cells prevent growth of pancreatic tumors through lysis and differentiation, thereby curtailing the growth and metastatic potential of stem-like/undifferentiated-tumors.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Anna Karolina Kozlowska
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
- Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Paytsar Topchyan
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Nick Ohanian
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Jessica Chiang
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Jessica Cook
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Phyu Ou Maung
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - So-Hyun Park
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
| | - Nicholas Cacalano
- The Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA;
- Department of Radiation Oncology, Division of Molecular and Cellular Oncology, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
| | - Changge Fang
- BioPro Diagnostics, LLC, 4919 Brook Hills Drive, Annandale, VA 22003, USA;
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Department of Dentistry, University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA; (K.K.); (A.K.K.); (P.T.); (M.-W.K.); (N.O.); (J.C.); (J.C.); (P.O.M.); (S.-H.P.)
- The Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA;
- Correspondence: ; Tel.: +1-310-968-4994; Fax: +1-310-794-7109
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25
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Jewett A, Kos J, Kaur K, Safaei T, Sutanto C, Chen W, Wong P, Namagerdi AK, Fang C, Fong Y, Ko MW. Natural Killer Cells: Diverse Functions in Tumor Immunity and Defects in Pre-neoplastic and Neoplastic Stages of Tumorigenesis. MOLECULAR THERAPY-ONCOLYTICS 2019; 16:41-52. [PMID: 31930165 PMCID: PMC6951836 DOI: 10.1016/j.omto.2019.11.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Natural killer (NK) cells are the key immune effectors with the ability to mediate selection and differentiation of a number of different cancer stem cells/undifferentiated tumors via lysis, and secreted or membrane-bound interferon (IFN)-γ and tumor necrosis factor (TNF)-α, respectively, leading to curtailment of tumor growth and metastasis. In this review, we present an overview of our recent findings on the biology and significance of NK cells in selection and differentiation of stem-like tumors using in vitro and in vivo studies conducted in humanized-BLT mice and in cancer patients. In addition, we present current advances in NK cell expansion and therapeutic delivery, and discuss the utility of allogeneic supercharged NK cells in the treatment of cancer patients. Moreover, we discuss the potential loss of NK cell numbers and function at the neoplastic and pre-neoplastic stages of tumorigenesis in induction and progression of pancreatic cancer. Therefore, because of their indispensable role in targeting cancer stem-like/undifferentiated tumors, NK cells should be placed high in the armamentarium of tumor immunotherapy. A combination of allogeneic supercharged NK cells with other immunotherapeutic strategies such as oncolytic viruses, antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies, checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, CAR NK cells, and chemotherapeutic and radiotherapeutic strategies can be used for the ultimate goal of tumor eradication.
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Affiliation(s)
- Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
- Corresponding author: Anahid Jewett, The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
| | - Janko Kos
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Tahmineh Safaei
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Christine Sutanto
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Wuyang Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Paul Wong
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Artin Keshishian Namagerdi
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Changge Fang
- APD-PAPD Center for NK Cell Therapy, Beijing, China
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
- Center for Gene Therapy, Duarte, CA, USA
- Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
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26
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Andrukhov O, Behm C, Blufstein A, Rausch-Fan X. Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: Implication in disease and tissue regeneration. World J Stem Cells 2019; 11:604-617. [PMID: 31616538 PMCID: PMC6789188 DOI: 10.4252/wjsc.v11.i9.604] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/24/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are considered as an attractive tool for tissue regeneration and possess a strong immunomodulatory ability. Dental tissue-derived MSCs can be isolated from different sources, such as the dental pulp, periodontal ligament, deciduous teeth, apical papilla, dental follicles and gingiva. According to numerous in vitro studies, the effect of dental MSCs on immune cells might depend on several factors, such as the experimental setting, MSC tissue source and type of immune cell preparation. Most studies have shown that the immunomodulatory activity of dental MSCs is strongly upregulated by activated immune cells. MSCs exert mostly immunosuppressive effects, leading to the dampening of immune cell activation. Thus, the reciprocal interaction between dental MSCs and immune cells represents an elegant mechanism that potentially contributes to tissue homeostasis and inflammatory disease progression. Although the immunomodulatory potential of dental MSCs has been extensively investigated in vitro, its role in vivo remains obscure. A few studies have reported that the MSCs isolated from inflamed dental tissues have a compromised immunomodulatory ability. Moreover, the expression of some immunomodulatory proteins is enhanced in periodontal disease and even shows some correlation with disease severity. MSC-based immunomodulation may play an essential role in the regeneration of different dental tissues. Therefore, immunomodulation-based strategies may be a very promising tool in regenerative dentistry.
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Affiliation(s)
- Oleh Andrukhov
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria.
| | - Christian Behm
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria
| | - Alice Blufstein
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria
| | - Xiaohui Rausch-Fan
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria
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27
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Pišlar A, Jewett A, Kos J. Cysteine cathepsins: Their biological and molecular significance in cancer stem cells. Semin Cancer Biol 2018; 53:168-177. [DOI: 10.1016/j.semcancer.2018.07.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 07/26/2018] [Accepted: 07/27/2018] [Indexed: 12/17/2022]
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28
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Jewett A, Kos J, Fong Y, Ko MW, Safaei T, Perišić Nanut M, Kaur K. NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis. Semin Cancer Biol 2018; 53:178-188. [PMID: 30081230 DOI: 10.1016/j.semcancer.2018.08.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/31/2018] [Accepted: 08/02/2018] [Indexed: 02/06/2023]
Abstract
We have recently shown that natural killer (NK) cells select and differentiate cancer stem cells (CSCs)/undifferentiated tumors via secreted and membrane bound IFN-gamma (IFN-γ) and TNF-alpha (TNF-α), preventing tumor growth and inducing remodeling of the tumor microenvironment. Since many conventional therapeutic strategies, including chemotherapy and radiotherapy remain fairly unsuccessful in treating CSCs/poorly differentiated tumors, there has been an increasing interest in NK cell-targeted immunotherapy for the treatment of aggressive tumors. In our recent studies, we used humanized-BLT (hu-BLT) mouse model with transplanted human bone marrow, liver and thymus to demonstrate the efficacy of adoptive transfer of ex vivo expanded, super-charged NK cells in selection and differentiation of stem-like tumors within the context of a fully reconstituted human immune system. Furthermore, we have demonstrated that CSCs differentiated with split-anergized NK cells prior to implantation in hu-BLT mice were not able to grow or metastasize. However, when NK cell-mediated tumor differentiation was blocked by the addition of antibodies to IFN-γ and TNF-α, tumors grew and metastasized. In this review, we present current advances in NK cell expansion and therapeutic delivery, and discuss the utility of allogeneic super-charged NK cells in treatment of cancer patients. In addition, NK suppression occurs not only at the stage of overt cancer, but also at the pre-neoplastic stage. Therefore, due to the indispensable role of NK cells in targeting CSCs/undifferentiated tumors and their role in differentiation of the tumors, NK cells should be placed high in the armamentarium of tumor immunotherapy.
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Affiliation(s)
- Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA.
| | - Janko Kos
- Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA; Center of Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Tahmineh Safaei
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | | | - Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
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29
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Kaur K, Nanut MP, Ko MW, Safaie T, Kos J, Jewett A. Natural killer cells target and differentiate cancer stem-like cells/undifferentiated tumors: strategies to optimize their growth and expansion for effective cancer immunotherapy. Curr Opin Immunol 2018; 51:170-180. [PMID: 29653339 DOI: 10.1016/j.coi.2018.03.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/06/2018] [Accepted: 03/22/2018] [Indexed: 01/27/2023]
Abstract
Natural killer (NK) cells are known to select and differentiate cancer stem-like cells/undifferentiated tumors via lysis, and secreted/membrane bound IFN-γ and TNF-α respectively, resulting in the control of tumor growth. Several in vivo mouse models including humanized-BLT mice have been used to study the biology and significance of NK cells in selection/differentiation of stem-like tumors within the context of a reconstituted human immune system. In addition, we discuss the evidence and significance of NK cell loss at the pre-neoplastic stage. Therefore, because of their indispensable role in targeting CSCs/undifferentiated tumors, NK-cells should be placed high in the armamentarium of tumor therapy.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | | | - Meng-Wei Ko
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Tahmineh Safaie
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Janko Kos
- Department of Biotechnology, Jozef Stefan Institute, Ljubljana, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA.
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Kaur K, Topchyan P, Kozlowska AK, Ohanian N, Chiang J, Maung PO, Park SH, Ko MW, Fang C, Nishimura I, Jewett A. Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs. Oncoimmunology 2018; 7:e1426518. [PMID: 29721395 DOI: 10.1080/2162402x.2018.1426518] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/03/2018] [Accepted: 01/07/2018] [Indexed: 01/01/2023] Open
Abstract
Therapeutic role of NK cells in solid tumors was challenged previously even though their role in hematological malignancies has clearly been established. Furthermore, functions and numbers of NK cells are greatly suppressed in oral cancer patients necessitating effective future NK immunotherapeutic strategies to aid in the control of disease. The humanized-BLT (hu-BLT) mice were used to implant stem-like/undifferentiated oral tumors to study the role of super-charged NK cells with and without feeding with AJ2 probiotic bacteria. Implanted CSC/undifferentiated tumors resected from NK-injected mice exhibited differentiated phenotype, grew slowly, and did not cause weight loss, whereas those from tumor-bearing mice without NK-injection remained relatively more stem-like/poorly-differentiated, grew faster, and caused significant weight loss. Moreover, in vitro NK-differentiated tumors were sensitive to chemotherapeutic drugs, and when implanted in the oral-cavity grew no or very small tumors in mice. When NK-mediated differentiation of tumors was blocked by IFN-γ and TNF-α antibodies before implantation, tumors grew rapidly, remained stem-like/poorly-differentiated and became resistant to chemotherapeutic drugs. Loss of NK cytotoxicity and decreased IFN-γ secretion in tumor-bearing mice in PBMCs, splenocytes, bone marrow derived immune cells and enriched NK cells was restored by the injection of super-charged NK cells with or without feeding with AJ2. Much greater infiltration of CD45+ and T cells were observed in tumors resected from the mice, along with the restored secretion of IFN-γ from purified T cells from splenocytes in NK-injected tumor-bearing mice fed with AJ2 probiotic bacteria. Thus, super-charged NK cells prevent tumor growth by restoring effector function resulting in differentiation of CSCs/undifferentiated-tumors in hu-BLT mice.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - Paytsar Topchyan
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - Anna Karolina Kozlowska
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA.,Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Nick Ohanian
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - Jessica Chiang
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - Phyu Ou Maung
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - So-Hyun Park
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA
| | - Changge Fang
- Pingan Advanced Personalized Diagnostics, Biomed Co. (USA and Beijing), Beijing, China
| | - Ichiro Nishimura
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA.,Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA.,The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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31
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Kozlowska AK, Topchyan P, Kaur K, Tseng HC, Teruel A, Hiraga T, Jewett A. Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs. J Cancer 2017; 8:537-554. [PMID: 28367234 PMCID: PMC5370498 DOI: 10.7150/jca.15989] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 07/24/2016] [Indexed: 01/04/2023] Open
Abstract
Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells. Treatment of oral tumors with sulindac, but not adriamycin inversely modulates the expression and function of NFκB and JNK, resulting in a significant down-regulation of IL-6, and VEGF secretion by oral tumor cells. In addition, increased secretion of IL-6 and VEGF is blocked by sulindac during interaction of oral tumors with NK cells. Sulindac treatment prevents synergistic induction of VEGF secretion by the tumor cells after their co-culture with untreated NK cells since non-activated NK cells lack the ability to efficiently kill tumor cells. Moreover, sulindac is able to profoundly reduce VEGF secretion by tumor cells cultured with IL-2 activated NK cells, which are able to significantly lyse the tumor cells. Based on the data presented in this study, we propose the following combinatorial approach for the treatment of stem-like/ poorly differentiated tumors in cancer patients with metastatic disease. Stem-like/ poorly differentiated tumor cells may in part undergo lysis or differentiation after NK cell immunotherapy, followed by treatment of differentiated tumors with chemotherapy and chemopreventive agents to eliminate the bulk of the tumor. This dual approach should limit tumor growth and prevent metastasis.
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Affiliation(s)
- Anna Karolina Kozlowska
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA.; Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Paytsar Topchyan
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA
| | - Kawaljit Kaur
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA
| | - Han-Ching Tseng
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA
| | - Antonia Teruel
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA
| | - Toru Hiraga
- Department of Histology and Cell Biology Matsumoto Dental University, Gobara-Hirooka, Shiojiri, Nagano, Japan
| | - Anahid Jewett
- The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA
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Ferreira-Teixeira M, Paiva-Oliveira D, Parada B, Alves V, Sousa V, Chijioke O, Münz C, Reis F, Rodrigues-Santos P, Gomes C. Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells. BMC Med 2016; 14:163. [PMID: 27769244 PMCID: PMC5075212 DOI: 10.1186/s12916-016-0715-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 10/06/2016] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND High-grade non-muscle invasive bladder cancer (NMIBC) has a high risk of recurrence and progression to muscle-invasive forms, which seems to be largely related to the presence of tumorigenic stem-like cell populations that are refractory to conventional therapies. Here, we evaluated the therapeutic potential of Natural Killer (NK) cell-based adoptive immunotherapy against chemoresistant bladder cancer stem-like cells (CSCs) in a pre-clinical relevant model, using NK cells from healthy donors and NMIBC patients. METHODS Cytokine-activated NK cells from healthy donors and from high-grade NMIBC patients were phenotypically characterized and assayed in vitro against stem-like and bulk differentiated bladder cancer cells. Stem-like cells were isolated from two bladder cancer cell lines using the sphere-forming assay. The in vivo therapeutic efficacy was evaluated in mice bearing a CSC-induced orthotopic bladder cancer. Animals were treated by intravesical instillation of interleukin-activated NK cells. Tumor response was evaluated longitudinally by non-invasive bioluminescence imaging. RESULTS NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition. In addition to cell killing, NK cells shifted CSCs towards a more differentiated phenotype, rendering them more susceptible to cisplatin, highlighting the benefits of a possible combined therapy. On the contrary, NK cells from NMIBC patients displayed a low density on NK cytotoxicity receptors, adhesion molecules and a more immature phenotype, losing their ability to kill and drive differentiation of CSCs. The local administration, via the transurethral route, of activated NK cells from healthy donors provides an efficient tumor infiltration and a subsequent robust tumoricidal activity against bladder cancer with high selective cytolytic activity against CSCs, leading to a dramatic reduction in tumor burden from 80 % to complete remission. CONCLUSION Although pre-clinical, our results strongly suggest that an immunotherapeutic strategy using allogeneic activated NK cells from healthy donors is effective and should be exploited as a complementary therapeutic strategy in high-risk NMIBC patients to prevent tumor recurrence and progression.
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Affiliation(s)
- Margarida Ferreira-Teixeira
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
| | - Daniela Paiva-Oliveira
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
| | - Belmiro Parada
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Urology and Renal Transplantation Department, Coimbra University Hospital Centre (CHUC), Coimbra, Portugal
| | - Vera Alves
- Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Vitor Sousa
- Service of Anatomical Pathology, Coimbra University Hospital Centre (CHUC), Coimbra, Portugal.,Institute of Anatomical and Molecular Pathology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Obinna Chijioke
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Christian Münz
- Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Flávio Reis
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
| | - Paulo Rodrigues-Santos
- Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Célia Gomes
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal. .,CNC.IBILI, University of Coimbra, Coimbra, Portugal. .,Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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Tseng HC, Kanayama K, Kaur K, Park SH, Park S, Kozlowska A, Sun S, McKenna CE, Nishimura I, Jewett A. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation. Oncotarget 2016; 6:20002-25. [PMID: 26343372 PMCID: PMC4652983 DOI: 10.18632/oncotarget.4755] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 07/16/2015] [Indexed: 11/25/2022] Open
Abstract
The aim of this study is to establish osteoclasts as key immune effectors capable of activating the function of Natural Killer (NK) cells, and expanding their numbers, and to determine in vivo and in vitro effect of bisphosphonates (BPs) during NK cell interaction with osteoclasts and on systemic and local immune function. The profiles of 27 cytokines, chemokines and growth factors released from osteoclasts were found to be different from dendritic cells and M1 macrophages but resembling to untreated monocytes and M2 macrophages. Nitrogen-containing BPs Zoledronate (ZOL) and Alendronate (ALN), but not non-nitrogen-containing BPs Etidronate (ETI), triggered increased release of pro-inflammatory mediators from osteoclasts while all three BPs decreased pit formation by osteoclasts. ZOL and ALN mediated significant release of IL-6, TNF-` and IL-1β, whereas they inhibited IL-10 secretion by osteoclasts. Treatment of osteoclasts with ZOL inhibited NK cell mediated cytotoxicity whereas it induced significant secretion of cytokines and chemokines. NK cells lysed osteoclasts much more than their precursor cells monocytes, and this correlated with the decreased expression of MHC class I expression on osteoclasts. Intravenous injection of ZOL in mice induced pro-inflammatory microenvironment in bone marrow and demonstrated significant immune activation. By contrast, tooth extraction wound of gingival tissues exhibited profound immune suppressive microenvironment associated with dysregulated wound healing to the effect of ZOL which could potentially be responsible for the pathogenesis of Osteonecrosis of the Jaw (ONJ). Finally, based on the data obtained in this paper we demonstrate that osteoclasts can be used as targets for the expansion of NK cells with superior function for immunotherapy of cancer.
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Affiliation(s)
- Han-Ching Tseng
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Keiichi Kanayama
- Division of Advanced Prosthodontics, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA.,Department of Periodontology, Asahi University School of Dentistry, Gifu, Japan
| | - Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | - So-Hyun Park
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Sil Park
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA.,Division of Advanced Prosthodontics, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Anna Kozlowska
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA.,Department of Tumor Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - Shuting Sun
- Department of Chemistry, University of Southern California, Los Angeles, CA, USA
| | - Charles E McKenna
- Department of Chemistry, University of Southern California, Los Angeles, CA, USA
| | - Ichiro Nishimura
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA.,Division of Advanced Prosthodontics, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA
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Kozlowska AK, Kaur K, Topchyan P, Jewett A. Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice. Cancer Immunol Immunother 2016; 65:835-45. [PMID: 27034236 DOI: 10.1007/s00262-016-1822-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 02/29/2016] [Indexed: 11/26/2022]
Abstract
Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice-a strategy that provides a much-needed platform to develop effective cancer immunotherapies.
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Affiliation(s)
- Anna K Kozlowska
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
- Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Paytsar Topchyan
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA, USA.
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.
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Bui VT, Tseng HC, Kozlowska A, Maung PO, Kaur K, Topchyan P, Jewett A. Augmented IFN-γ and TNF-α Induced by Probiotic Bacteria in NK Cells Mediate Differentiation of Stem-Like Tumors Leading to Inhibition of Tumor Growth and Reduction in Inflammatory Cytokine Release; Regulation by IL-10. Front Immunol 2015; 6:576. [PMID: 26697005 PMCID: PMC4667036 DOI: 10.3389/fimmu.2015.00576] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 10/26/2015] [Indexed: 12/31/2022] Open
Abstract
Our previous reports demonstrated that the magnitude of natural killer (NK) cell-mediated cytotoxicity correlate directly with the stage and level of differentiation of tumor cells. In addition, we have shown previously that activated NK cells inhibit growth of cancer cells through induction of differentiation, resulting in the resistance of tumor cells to NK cell-mediated cytotoxicity through secreted cytokines, as well as direct NK-tumor cell contact. In this report, we show that in comparison to IL-2 + anti-CD16mAb-treated NK cells, activation of NK cells by probiotic bacteria (sAJ2) in combination with IL-2 and anti-CD16mAb substantially decreases tumor growth and induces maturation, differentiation, and resistance of oral squamous cancer stem cells, MIA PaCa-2 stem-like/poorly differentiated pancreatic tumors, and healthy stem cells of apical papillae through increased secretion of IFN-γ and TNF-α, as well as direct NK-tumor cell contact. Tumor resistance to NK cell-mediated killing induced by IL-2 + anti-CD16mAb + sAJ2-treated NK cells is induced by combination of IFN-γ and TNF-α since antibodies to both, and not each cytokine alone, were able to restore tumor sensitivity to NK cells. Increased surface expression of CD54, B7H1, and MHC-I on NK-differentiated tumors was mediated by IFN-γ since the addition of anti-IFN-γ abolished their increase and restored the ability of NK cells to trigger cytokine and chemokine release; whereas differentiated tumors inhibited cytokine release by the NK cells. Monocytes synergize with NK cells in the presence of probiotic bacteria to induce regulated differentiation of stem cells through secretion of IL-10 resulting in resistance to NK cell-mediated cytotoxicity and inhibition of cytokine release. Therefore, probiotic bacteria condition activated NK cells to provide augmented differentiation of cancer stem cells resulting in inhibition of tumor growth, and decreased inflammatory cytokine release.
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Affiliation(s)
- Vickie T. Bui
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
| | - Han-Ching Tseng
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
| | - Anna Kozlowska
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
- Department of Tumor Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - Phyu Ou Maung
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
| | - Kawaljit Kaur
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
| | - Paytsar Topchyan
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California Los Angeles, Los Angeles, CA, USA
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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Gras Navarro A, Björklund AT, Chekenya M. Therapeutic potential and challenges of natural killer cells in treatment of solid tumors. Front Immunol 2015; 6:202. [PMID: 25972872 PMCID: PMC4413815 DOI: 10.3389/fimmu.2015.00202] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 04/14/2015] [Indexed: 12/22/2022] Open
Abstract
Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.
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Affiliation(s)
| | - Andreas T Björklund
- Karolinska University Hospital, Hematology Center and Karolinska Institute , Stockholm , Sweden
| | - Martha Chekenya
- Department of Biomedicine, University of Bergen , Bergen , Norway
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