13 results on '"Kaur, Kawaljit"'
Search Results
2. Osteoclast-expanded super-charged NK-cells preferentially select and expand CD8+ T cells.
- Author
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Kaur K, Ko MW, Ohanian N, Cook J, and Jewett A
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Carcinoma, Squamous Cell immunology, Carcinoma, Squamous Cell pathology, Cell Communication immunology, Cell Proliferation, Coculture Techniques, Dendritic Cells immunology, Dendritic Cells pathology, Humans, Immunophenotyping, Interferon-gamma biosynthesis, Interferon-gamma immunology, Killer Cells, Natural pathology, Killer Cells, Natural transplantation, Lymphocyte Activation, Lymphocyte Count, Mice, Mice, Transgenic, Mouth Neoplasms immunology, Mouth Neoplasms pathology, Osteoclasts pathology, Primary Cell Culture, Xenograft Model Antitumor Assays, Carcinoma, Squamous Cell therapy, Cytotoxicity, Immunologic, Immunotherapy methods, Killer Cells, Natural immunology, Mouth Neoplasms therapy, Osteoclasts immunology
- Abstract
Osteoclasts (OCs) and much less dendritic cells (DCs) induce significant expansion and functional activation of NK cells, and furthermore, the OC-expanded NK cells preferentially increase the expansion and activation of CD8+ T cells by targeting CD4+ T cells. When autologous OCs were used to expand patient NK cells much lower percentages of expanded CD8+ T cells, decreased numbers of expanded NK cells and decreased functions of NK cells could be observed, and the addition of allogeneic healthy OCs increased the patients' NK function. Mechanistically, OC-expanded NK cells were found to lyse CD4+ T cells but not CD8+ T cells suggesting potential selection of CD8+ T cells before their expansion by OC activated NK cells. In agreement, Increased IFN-γ secretion, and NK cell-mediated cytotoxicity and higher percentages of CD8+ T cells, in various tissue compartments of oral tumor-bearing hu-BLT mice in response to immunotherapy by OC-expanded NK cells were observed. Thus, our results indicate an important relationship between NK and CD8+ T cells.
- Published
- 2020
- Full Text
- View/download PDF
3. Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice.
- Author
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Kozlowska AK, Kaur K, Topchyan P, and Jewett A
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- Animals, Disease Models, Animal, Humans, Mice, Tumor Microenvironment, Immunotherapy, Adoptive methods, Killer Cells, Natural immunology, Neoplasms immunology, Neoplasms therapy, Neoplastic Stem Cells immunology, Osteoclasts immunology
- 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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- 2016
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4. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation.
- Author
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Tseng HC, Kanayama K, Kaur K, Park SH, Park S, Kozlowska A, Sun S, McKenna CE, Nishimura I, and Jewett A
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- Alendronate pharmacology, Animals, Apoptosis drug effects, Bone Marrow immunology, Cell Communication drug effects, Cell Communication immunology, Cell Differentiation drug effects, Cell Differentiation immunology, Female, Gingiva immunology, Humans, Imidazoles pharmacology, Killer Cells, Natural immunology, Macrophages drug effects, Macrophages immunology, Mice, Mice, Inbred C57BL, Monocytes drug effects, Monocytes immunology, Osteoclasts immunology, Zoledronic Acid, Bone Marrow drug effects, Diphosphonates pharmacology, Gingiva drug effects, Killer Cells, Natural drug effects, Osteoclasts drug effects
- 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.
- Published
- 2015
- Full Text
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5. Osteoclasts and Probiotics Mediate Significant Expansion, Functional Activation and Supercharging in NK, γδ T, and CD3+ T Cells: Use in Cancer Immunotherapy
- Author
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Kaur, Kawaljit and Jewett, Anahid
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Cancer ,Human Fetal Tissue ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,Animals ,Mice ,Osteoclasts ,Killer Cells ,Natural ,Immunotherapy ,Neoplasms ,Antineoplastic Agents ,Probiotics ,osteoclasts ,NK cells ,supercharged NK cells ,CD3+T cells ,gamma delta T cells ,IFN-gamma ,humanized-BLT mice ,CD3+ T cells ,IFN-γ ,γδ T cells ,Biological sciences ,Biomedical and clinical sciences - Abstract
Our previous studies have introduced osteoclasts (OCs) as major activators of NK cells. It was found that OCs exhibit the capabilities of inducing cell expansion as well as increasing the cytotoxic activity of NK cells by granule release and increasing the secretion of TNF-α and TRAIL, leading to increased lysis of tumors in short-term as well as long-term periods, respectively. OC- induced expanded NK cells were named supercharged NK cells (sNK) due to their significantly high functional activity as well as their significantly higher cell expansion rate. It is, however, unclear whether the OC-mediated effect in NK cells is specific or whether other cytotoxic immune cells can also be expanded and activated by OCs. We chose to focus on γδ T cells and pan T cells, which also include CD8+ T cells. In this paper, we report that OCs are capable of expanding and functionally activating both γδ T cells and pan T cells. Expanded γδ T and pan T cells were capable of secreting high levels of INF-γ, albeit with different dynamics to those of NK cells, and, moreover, they are unable to kill NK-specific targets. Since we used humanized-BLT (hu-BLT) mice as a model of human disease, we next determined whether NK and T cell activation through OCs is also evident in cells obtained from hu-BLT mice. Similar to humans, OCs were capable of increasing the cell expansion and secretion of IFN-γ in the culture of either NK or T cells from hu-BLT mice, providing yet further evidence that these mice are appropriate models to study human disease. Therefore, these studies indicated that CD3+ T or γδ T cells can proliferate and be supercharged by OCs similar to the NK cells; thus, they can be used individually or in combination in the cell therapy of cancers.
- Published
- 2024
6. Differences in Tumor Growth and Differentiation in NSG and Humanized-BLT Mice; Analysis of Human vs. Humanized-BLT-Derived NK Expansion and Functions
- Author
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Kaur, Kawaljit and Jewett, Anahid
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Human Fetal Tissue ,Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,IFN-gamma ,NK cells ,cytotoxicity ,cancer ,humanized-BLT (hu-BLT) mice ,NSG mice ,osteoclasts ,OC-expanded super-charged NK cells ,IFN-γ ,Oncology and Carcinogenesis ,Oncology and carcinogenesis - 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.
- Published
- 2023
7. 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.
- Author
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Kaur, Kawaljit, Safaie, Tahmineh, Ko, Meng-Wei, Wang, Yuhao, and Jewett, Anahid
- Subjects
IFN-γ ,MICA/B mAb ,NK cells ,antibody-dependent cellular cytotoxicity (ADCC) ,cancer stem cells (CSCs) ,cytotoxicity ,differentiation ,humanized-BLT mice ,osteoclasts - 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.
- Published
- 2021
8. Natural Killer Cells: Diverse Functions in Tumor Immunity and Defects in Pre-neoplastic and Neoplastic Stages of Tumorigenesis.
- Author
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Jewett, Anahid, Kos, Janko, Kaur, Kawaljit, Safaei, Tahmineh, Sutanto, Christine, Chen, Wuyang, Wong, Paul, Namagerdi, Artin, Fang, Changge, Fong, Yuman, and Ko, Meng-Wei
- Subjects
CSCs ,KRAS ,NK cells ,cancer immunotherapy ,cancer stem cells ,differentiation ,humanized-BLT mice ,osteoclasts ,pre-neoplastic ,supercharged NK cells - 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.
- Published
- 2020
9. Deficiencies in Natural Killer Cell Numbers, Expansion, and Function at the Pre-Neoplastic Stage of Pancreatic Cancer by KRAS Mutation in the Pancreas of Obese Mice
- Author
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Kaur, Kawaljit, Chang, Hui-Hua, Topchyan, Paytsar, Cook, Jessica Morgan, Barkhordarian, Andre, Eibl, Guido, and Jewett, Anahid
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Digestive Diseases ,Nutrition ,Obesity ,Cancer ,Rare Diseases ,Pancreatic Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Metabolic and endocrine ,Adipose Tissue ,Animals ,Biomarkers ,Cytokines ,Cytotoxicity ,Immunologic ,Disease Models ,Animal ,Immunophenotyping ,Killer Cells ,Natural ,Leukocyte Count ,Mice ,Mice ,Knockout ,Mice ,Obese ,Mutation ,Osteoclasts ,Pancreatic Neoplasms ,Precancerous Conditions ,Proto-Oncogene Proteins p21(ras) ,Spleen ,natural killer cells ,KRAS ,IFN-gamma ,HFCD ,control diet ,pre-neoplastic lesions ,IFN-γ ,Medical Microbiology ,Biochemistry and cell biology ,Genetics - Abstract
The combined/synergistic effect of genetic mutation of KRAS in the pancreas and obesity, a life-style factor on suppression of natural killer (NK) cells at the pre-neoplastic stage of pancreatic cancer has not been investigated and is the subject of this report. Obese mice with KRAS (KC) mutation in the pancreas fed with high-fat calorie diet (HFCD) exhibit severe deficiencies in the NK cell expansion and function at the pre-neoplastic stage of pancreatic cancer. Decreased NK cell-mediated cytotoxicity is observed in the peripheral blood, spleen, pancreas, and peri-pancreatic adipose tissue in obese KC mice, whereas in bone marrow an increased NK cell-mediated cytotoxicity is observed when compared to lean WT mice fed with control diet (CD). Obese KC mice on HFCD demonstrated the least ability to expand NK cells or induce NK cell-mediated cytotoxicity when compared to the other groups of mice. Indeed, the following profile WT/CD > WT/HFCD > KC/CD > KC/HFCD was seen for the ability to expand NK cells or mediate cytotoxicity among four groups of mice in spleen, peripheral blood, pancreas, and peri-pancreatic adipose tissue. Sorted NK cells from the splenocytes of four groups of mice also exhibited the same profiles for the cytotoxicity as the unsorted splenocytes, and a decreased IFN-γ secretion could be seen in cultures of NK cells from KC mice fed with either CD or HFCD. Cultures of NK cells with autologous monocytes from obese KC mice fed with HFCD exhibited decreased cytotoxicity and IFN-γ secretion, whereas cultures of allogeneic NK cells from WT mice fed with CD with osteoclasts of obese mice fed with HFCD demonstrated decreased cytotoxicity but augmented IFN-γ secretion. Increased IL-6 along with decreased IFN-γ and cell-mediated cytotoxicity by the NK cells, within NK-adipose tissue of KC/HFCD mice, may provide safe microenvironment for the expansion of pancreatic tumors.
- Published
- 2018
10. Osteonecrosis of the Jaw Developed in Mice DISEASE VARIANTS REGULATED BY γδ T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY*
- Author
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Park, Sil, Kanayama, Keiichi, Kaur, Kawaljit, Tseng, Han-Ching Helen, Banankhah, Sina, Quje, Davood Talebi, Sayre, James W, Jewett, Anahid, and Nishimura, Ichiro
- Subjects
Dental/Oral and Craniofacial Disease ,2.1 Biological and endogenous factors ,Aetiology ,Oral and gastrointestinal ,Animals ,Bisphosphonate-Associated Osteonecrosis of the Jaw ,Bone Density Conservation Agents ,DNA-Binding Proteins ,Diphosphonates ,Disease Models ,Animal ,Female ,Humans ,Imidazoles ,Immunity ,Mucosal ,In Vitro Techniques ,Jaw ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mouth Mucosa ,Osteoclasts ,Receptors ,Antigen ,T-Cell ,gamma-delta ,Risk Factors ,T-Lymphocyte Subsets ,Tooth Extraction ,Wound Healing ,X-Ray Microtomography ,Zoledronic Acid ,ONJ ,T cell ,bisphosphonate ,mouse ,mucosal immunology ,osteonecrosis ,pathogenesis ,wound healing ,γδ T cells ,Chemical Sciences ,Biological Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology - Abstract
Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.
- Published
- 2015
11. Super-charged NK cells increase immune infiltration in the tumor microenvironment and inhibit tumor growth in humanized-BLT mice
- Author
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Kaur, Kawaljit
- Subjects
Health sciences ,humanized-BLT ,IFN-gamma ,NK cells ,Osteoclasts ,sAJ2 ,Super-charged NKs - Abstract
NK cells are known to limit growth and expansion of cancer stem cells and oral tumors by providing key cytokines such as IFN-γ and TNF-α, which drive differentiation of stem-like/poorly differentiated cancer stem cells. The detailed understanding of how and why their function is affected by the cancer microenvironment is very important for outlining the most efficient NK cell-based immunotherapies for cancer patients. In this regard, we first characterized NK cells from the cancer patients for their IFN-γ secretion, cytotoxic function against the cancer stem cells, and their surface receptors. In previous studies, we demonstrated that IFN-γ plays a dominant role in up-regulation of B7H1, CD54 and MHC1 surface receptor expression and inhibition of tumor growth by differentiating the cancer stem cells, and via inflammatory cytokine release when they are in contact with cancer stem cells. We also showed that induction of NK cell-mediated cytotoxicity resistance and differentiation in the stem cells correlated with the increased expression of CD54, B7H1, and MHCI, and mediated by the combination of membrane-bound or secreted IFN-γ. In this study, we demonstrated that NK media adjusted based cells from cancer patients secreted lower IFN-γ. When we used the NK cell condition media from the cancer patient and healthy NK cells to treat the cancer stem cells, the condition media from cancer patient NK cells was less capable of differentiating the cancer stem cells. The cancer stem cells treated with patient NK cells condition media, were more susceptible to NK cell-mediated cytotoxicity and displayed lower surface expression of CD54, MHC1, and B7H1 when compared to cancer stem cells treated with healthy IFN-γ. We also demonstrated that among all the cells we characterized to design a novel strategy to expand highly potent NK cells, osteoclasts fit best based on the NK receptors ligand expression and secreted cytokines required for NK cells expansion and activation. In this regard, we tested the cancer patient osteoclasts (OCs) for their surface expression of MHC1 and MICA/B, both were showed lower expression levels on cancer patient OCs. So, not just the NK cells receptors required for tumor recognition are lower on cancer patient NK cells, but the ligands required to increase the expression of those receptors are also down-modulated in cancer patient OCs. Next, we cultured the cancer patient NK cells with healthy donor OCs, and we were able to increase the surface expression of NKG2D on patient NK cells but, again the cytotoxic activity and IFN-γ were lower in patient NK cells. We confirmed our finding by analyzing the OCs from KRAS mutated mice and hu-BLT mice injected with tumor. Based on our data, we were not convinced in the use of autologous NK cells to treat the cancer patients, our strategy was to use expanded allogenic NK cells as cancer cell immunotherapy. Next, we tested the expanded allogeneic NK cells in tumor implanted hu-BLT mice. With just one NK cell injection (1.5 million cells), tumor growth was inhibited in the mice. On analyzing the immune cell compartments, NK cell-mediated cytotoxicity and IFN-γ from immune cells was improved significantly. Tumors dissected from animals that received NK therapy showed differentiation profile, high MHC1, CD54 and B7H1 on their surface and lower growth in the culture when compared to tumor dissected from hu-BLT mice without NK cell immunotherapy. It has been known that mature alloreactive NK cells can be safely infused into patients with no increased incidence of graft versus host disease (GvDH). To avoid any kind of risk of GvHD, we can also consider isolating the contaminating T cells from the super-charged NK cells, and injecting the high purity NK cells.
- Published
- 2017
12. Novel Strategy to Expand Super-Charged NK Cells with Significant Potential to Lyse and Differentiate Cancer Stem Cells: Differences in NK Expansion and Function between Healthy and Cancer Patients.
- Author
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Kaur, Kawaljit, Cook, Jessica, So-Hyun Park, Topchyan, Paytsar, Kozlowska, Anna, Ohanian, Nick, Changge Fang, Ichiro Nishimura, and Jewett, Anahid
- Subjects
KILLER cells ,CANCER stem cells ,CELL-mediated cytotoxicity ,OSTEOCLASTS ,INTERFERONS - Abstract
Natural killer (NK) cells are known to target cancer stem cells and undifferentiated tumors. In this paper, we provide a novel strategy for expanding large numbers of super-charged NK cells with significant potential to lyse and differentiate cancer stem cells and demonstrate the differences in the dynamics of NK cell expansion between healthy donors and cancer patients. Decline in cytotoxicity and lower interferon (IFN)-γ secretion by osteoclast (OC)-expanded NK cells from cancer patients correlates with faster expansion of residual contaminating T cells within purified NK cells, whereas healthy donors' OCs continue expanding super-charged NK cells while limiting T cell expansion for up to 60 days. Similar to patient NK cells, NK cells from tumor-bearing BLT-humanized mice promote faster expansion of residual T cells resulting in decreased numbers and function of NK cells, whereas NK cells from mice with no tumor continue expanding NK cells and retain their cytotoxicity. In addition, dendritic cells (DCs) in contrast to OCs are found to promote faster expansion of residual T cells within purified NK cells resulting in the decline in NK cell numbers from healthy individuals. Addition of anti-CD3 mAb inhibits T cell proliferation while enhancing NK cell expansion; however, expanding NK cells have lower cytotoxicity but higher secretion of IFN-γ. Expansion and functional activation of super-charged NK cells by OCs is dependent on interleukin (IL)-12 and IL-15. Thus, in this report, we not only provide a novel strategy to expand super-charged NK cells, but also demonstrate that rapid and sustained expansion of residual T cells within the purified NK cells during expansion with DCs or OCs could be a potential mechanism by which the numbers and function of NK cells decline in cancer patients and in BLT-humanized mice. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
13. Zoledronic acid mediated differential activation of NK cells in different organs of WT and Rag2-/- mice; stark differences between the bone marrow and gingivae.
- Author
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Kaur, Kawaljit, Kanayama, Keiichi, Wu, Qing-Qing, Gumrukcu, Serhat, Nishimura, Ichiro, and Jewett, Anahid
- Subjects
- *
KILLER cells , *BONE marrow , *GINGIVA , *CELL-mediated cytotoxicity , *BONE marrow cells , *ZOLEDRONIC acid - Abstract
• Increased IFN-γ secretion in Rag2-/- mice versus WT mice, with the exception of the gingivae. • In Rag2-/- mice, ZOL injection and tooth extraction stimulated IFN-γ secretion from BM immune cells but inhibited IFN-γ secretion from both spleen and gingivae. • In both WT and Rag2-/- mice, immune cells from gingivae exhibited decreased IFN-γ secretion with ZOL injection. We have previously shown that natural killer (NK) cells expand, and increase their function after interaction with cells that exhibit a number of different knock-down genes. We hypothesized that deletion or knockdown of a variety of key genes such as RAG may cause de-differentiation of the cells which could lead to increased NK expansion and function since we have shown previously that NK cells are activated and expanded by less differentiated cells. When comparing the function of NK cells from bone marrow (BM), spleen, pancreas, adipose tissue, and gingiva from WT mice to those from Rag2-/- mice, we observed a significant increase in IFN-γ secretion in all tissues of Rag2-/- mice versus in WT mice, with the exception of the gingivae in which similar levels were observed. After injecting WT mice with zoledronic acid (ZOL) and tooth extraction, immune cells from BM, spleen, and purified NK cells from spleen exhibited very high induction of IFN-γ and NK cell-mediated cytotoxicity with the exception of gingiva in which immune cells exhibited the opposite. In Rag2-/- mice, ZOL injection and tooth extraction stimulated IFN-γ secretion from BM immune cells but inhibited IFN-γ secretion from both spleen and gingivae. In both WT and Rag2-/- mice, immune cells from gingivae exhibited decreased IFN-γ secretion when activated, indicating significant regulation of immune cell function in the gingival microenvironment. However, even though significantly lower induction of IFN-γ was observed in both WT and Rag2-/- gingival cells after ZOL injection, ZOL mediated secretion of IFN-γ was still higher in the gingivae of WT mice when compared to those of Rag2-/- gingival cells. These results suggest an important role for IFN-γ in the pathogenesis of osteonecrosis lesions observed in post-tooth extraction jawbone. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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