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Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms.
Yang J, Kumar A, Vilgelm AE, Chen SC, Ayers GD, Novitskiy SV, Joyce S, Richmond A
(2018) Cancer Immunol Res 6: 1186-1198
MeSH Terms: Animals, Bone Marrow Transplantation, Cell Line, Tumor, Cytotoxicity, Immunologic, Fas Ligand Protein, Interleukin-18, Killer Cells, Natural, Macrophages, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Receptors, CXCR4
Show Abstract · Added December 20, 2018
The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4 mice exhibited slowed tumor progression compared with CXCR4 mice in an inducible melanocyte mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4 mice as compared with myeloid cells from CXCR4 mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4 mice. NK cells from CXCR4 mice also exhibited increased tumor cell killing capacity , based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4 neutrophils. Furthermore, enhanced NK cell activity in CXCR4 mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4 mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. .
©2018 American Association for Cancer Research.
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13 MeSH Terms
Strategies to overcome therapeutic resistance in renal cell carcinoma.
Siska PJ, Beckermann KE, Rathmell WK, Haake SM
(2017) Urol Oncol 35: 102-110
MeSH Terms: Angiogenesis Inhibitors, Antineoplastic Agents, Carcinoma, Renal Cell, Clinical Trials as Topic, Costimulatory and Inhibitory T-Cell Receptors, Cytotoxicity, Immunologic, Disease Progression, Disease-Free Survival, Drug Resistance, Neoplasm, Humans, Immunotherapy, Kidney, Kidney Neoplasms, Neoplasm Recurrence, Local, Neovascularization, Pathologic, Nephrectomy, Protein Kinase Inhibitors, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, TOR Serine-Threonine Kinases
Show Abstract · Added April 18, 2017
BACKGROUND - Renal cell cancer (RCC) is a prevalent and lethal disease. At time of diagnosis, most patients present with localized disease. For these patients, the standard of care includes nephrectomy with close monitoring thereafter. While many patients will be cured, 5-year recurrence rates range from 30% to 60%. Furthermore, nearly one-third of patients present with metastatic disease at time of diagnosis. Metastatic disease is rarely curable and typically lethal. Cytotoxic chemotherapy and radiation alone are incapable of controlling the disease. Extensive effort was expended in the development of cytokine therapies but response rates remain low. Newer agents targeting angiogenesis and mTOR signaling emerged in the 2000s and revolutionized patient care. While these agents improve progression free survival, the development of resistance is nearly universal. A new era of immunotherapy is now emerging, led by the checkpoint inhibitors. However, therapeutic resistance remains a complex issue that is likely to persist.
METHODS AND PURPOSE - In this review, we systematically evaluate preclinical research and clinical trials that address resistance to the primary RCC therapies, including anti-angiogenesis agents, mTOR inhibitors, and immunotherapies. As clear cell RCC is the most common adult kidney cancer and has been the focus of most studies, it will be the focus of this review.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.
Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER
(2015) J Immunol 195: 2353-64
MeSH Terms: Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Body Temperature, CD8-Positive T-Lymphocytes, Cell Proliferation, Cytotoxicity, Immunologic, Dose-Response Relationship, Drug, Female, Flow Cytometry, Granzymes, Humans, Interferon-gamma, Interleukin-15, Interleukin-15 Receptor alpha Subunit, Killer Cells, Natural, Lectins, C-Type, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Perforin
Show Abstract · Added October 18, 2015
IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
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22 MeSH Terms
Anti-leukemic potency of piggyBac-mediated CD19-specific T cells against refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.
Saito S, Nakazawa Y, Sueki A, Matsuda K, Tanaka M, Yanagisawa R, Maeda Y, Sato Y, Okabe S, Inukai T, Sugita K, Wilson MH, Rooney CM, Koike K
(2014) Cytotherapy 16: 1257-69
MeSH Terms: Antigens, CD19, Cancer Vaccines, Cell Line, Tumor, Cell Proliferation, Culture Media, Serum-Free, Cytotoxicity, Immunologic, DNA Transposable Elements, Drug Resistance, Neoplasm, Genetic Engineering, Genetic Vectors, Humans, Immunotherapy, Adoptive, Interleukin-15, Interleukin-2, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutation, Protein Kinase Inhibitors, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, T-Lymphocytes, TNF-Related Apoptosis-Inducing Ligand, Up-Regulation
Show Abstract · Added October 28, 2014
BACKGROUND AIMS - To develop a treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant to tyrosine kinase inhibitors (TKIs), we evaluated the anti-leukemic activity of T cells non-virally engineered to express a CD19-specific chimeric antigen receptor (CAR).
METHODS - A CD19.CAR gene was delivered into mononuclear cells from 10 mL of blood of healthy donors through the use of piggyBac-transposons and the 4-D Nucleofector System. Nucleofected cells were stimulated with CD3/CD28 antibodies, magnetically selected for the CD19.CAR, and cultured in interleukin-15-containing serum-free medium with autologous feeder cells for 21 days. To evaluate their cytotoxic potency, we co-cultured CAR T cells with seven Ph(+)ALL cell lines including three TKI-resistant (T315I-mutated) lines at an effector-to-target ratio of 1:5 or lower without cytokines.
RESULTS - We obtained ∼1.3 × 10(8) CAR T cells (CD4(+), 25.4%; CD8(+), 71.3%), co-expressing CD45RA and CCR7 up to ∼80%. After 7-day co-culture, CAR T cells eradicated all tumor cells at the 1:5 and 1:10 ratios and substantially reduced tumor cell numbers at the 1:50 ratio. Kinetic analysis revealed up to 37-fold proliferation of CAR T cells during a 20-day culture period in the presence of tumor cells. On exposure to tumor cells, CAR T cells transiently and reproducibly upregulated the expression of transgene as well as tumor necrosis factor-related apoptosis-inducing ligand and interleukin-2.
CONCLUSIONS - We generated a clinically relevant number of CAR T cells from 10 mL of blood through the use of piggyBac-transposons, a 4D-Nulcleofector, and serum/xeno/tumor cell/virus-free culture system. CAR T cells exhibited marked cytotoxicity against Ph(+)ALL regardless of T315I mutation. PiggyBac-mediated CD19-specific T-cell therapy may provide an effective, inexpensive and safe option for drug-resistant Ph(+)ALL.
Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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22 MeSH Terms
ERAAP and tapasin independently edit the amino and carboxyl termini of MHC class I peptides.
Kanaseki T, Lind KC, Escobar H, Nagarajan N, Reyes-Vargas E, Rudd B, Rockwood AL, Van Kaer L, Sato N, Delgado JC, Shastri N
(2013) J Immunol 191: 1547-55
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Antigen Presentation, CD8-Positive T-Lymphocytes, Cells, Cultured, Consensus Sequence, Cytotoxicity, Immunologic, Endoplasmic Reticulum, Epitopes, T-Lymphocyte, Female, H-2 Antigens, Histocompatibility Antigen H-2D, Histocompatibility Antigens Class I, Leucyl Aminopeptidase, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Peptide Fragments, Proteasome Endopeptidase Complex
Show Abstract · Added March 7, 2014
Effective CD8(+) T cell responses depend on presentation of a stable peptide repertoire by MHC class I (MHC I) molecules on the cell surface. The overall quality of peptide-MHC I complexes (pMHC I) is determined by poorly understood mechanisms that generate and load peptides with appropriate consensus motifs onto MHC I. In this article, we show that both tapasin (Tpn), a key component of the peptide loading complex, and the endoplasmic reticulum aminopeptidase associated with Ag processing (ERAAP) are quintessential editors of distinct structural features of the peptide repertoire. We carried out reciprocal immunization of wild-type mice with cells from Tpn- or ERAAP-deficient mice. Specificity analysis of T cell responses showed that absence of Tpn or ERAAP independently altered the peptide repertoire by causing loss as well as gain of new pMHC I. Changes in amino acid sequences of MHC-bound peptides revealed that ERAAP and Tpn, respectively, defined the characteristic amino and carboxy termini of canonical MHC I peptides. Thus, the optimal pMHC I repertoire is produced by two distinct peptide editing steps in the endoplasmic reticulum.
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21 MeSH Terms
T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells.
Sandy AR, Chung J, Toubai T, Shan GT, Tran IT, Friedman A, Blackwell TS, Reddy P, King PD, Maillard I
(2013) J Immunol 190: 5818-28
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Enzyme Activation, Gene Expression Regulation, Graft vs Host Disease, Interferon-gamma, Lymphocyte Activation, Mice, Mitogen-Activated Protein Kinases, NF-kappa B, Proto-Oncogene Proteins p21(ras), Receptors, Notch, T-Box Domain Proteins, T-Lymphocytes, Regulatory
Show Abstract · Added March 7, 2014
Graft-versus-host disease (GVHD) induced by donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). We previously reported that the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML) markedly decreased the severity and mortality of acute GVHD mediated by CD4(+) T cells in mice. To elucidate the mechanisms of Notch action in GVHD and its role in CD8(+) T cells, we studied the effects of Notch inhibition in alloreactive CD4(+) and CD8(+) T cells using mouse models of allo-BMT. DNMAML blocked GVHD induced by either CD4(+) or CD8(+) T cells. Both CD4(+) and CD8(+) Notch-deprived T cells had preserved expansion in lymphoid organs of recipients, but profoundly decreased IFN-γ production despite normal T-bet and enhanced Eomesodermin expression. Alloreactive DNMAML T cells exhibited decreased Ras/MAPK and NF-κB activity upon ex vivo restimulation through the TCR. In addition, alloreactive T cells primed in the absence of Notch signaling had increased expression of several negative regulators of T cell activation, including Dgka, Cblb, and Pdcd1. DNMAML expression had modest effects on in vivo proliferation but preserved overall alloreactive T cell expansion while enhancing accumulation of pre-existing natural regulatory T cells. Overall, DNMAML T cells acquired a hyporesponsive phenotype that blocked cytokine production but maintained their expansion in irradiated allo-BMT recipients, as well as their in vivo and ex vivo cytotoxic potential. Our results reveal parallel roles for Notch signaling in alloreactive CD4(+) and CD8(+) T cells that differ from past reports of Notch action and highlight the therapeutic potential of Notch inhibition in GVHD.
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16 MeSH Terms
NK cells inhibit T-bet-deficient, autoreactive Th17 cells.
Wu W, Shi S, Ljunggren HG, Cava AL, Van Kaer L, Shi FD, Liu R
(2012) Scand J Immunol 76: 559-66
MeSH Terms: Animals, Autoantigens, Cell Communication, Cell Differentiation, Cells, Cultured, Cytokines, Cytotoxicity, Immunologic, Gene Expression Regulation, Immune Tolerance, Killer Cells, Natural, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Receptor Subfamily 1, Group F, Member 3, STAT3 Transcription Factor, T-Box Domain Proteins, Th1 Cells, Th17 Cells
Show Abstract · Added March 20, 2014
The differentiation and maintenance of Th17 cells require a unique cytokine milieu and activation of lineage-specific transcription factors. This process appears to be antagonized by the transcription factor T-bet, which controls the differentiation of Th1 cells. Considering that T-bet-deficient (T-bet(-/-) ) mice are largely devoid of natural killer (NK) cells due to a defect in the terminal maturation of these cells, and because NK cells can influence the differentiation of T helper cells, we investigated whether the absence of NK cells in T-bet-deficient mice contributes to the augmentation of autoreactive Th17 cell responses. We show that the loss of T-bet renders the transcription factors Rorc and STAT3 highly responsive to activation by stimuli provided by NK cells. Furthermore, reconstitution of T-bet(-/-) mice with wild-type NK cells inhibited the development of autoreactive Th17 cells through NK cell-derived production of IFN-γ. These results identify NK cells as critical regulators in the development of autoreactive Th17 cells and Th17-mediated pathology.
© 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd.
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18 MeSH Terms
5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection.
Secatto A, Rodrigues LC, Serezani CH, Ramos SG, Dias-Baruffi M, Faccioli LH, Medeiros AI
(2012) PLoS One 7: e31701
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Cell Proliferation, Cells, Cultured, Cytotoxicity, Immunologic, Flow Cytometry, Histoplasma, Histoplasmosis, Immunity, Humoral, Immunity, Innate, Leukotriene B4, Leukotriene C4, Lung, Lymphocyte Activation, Macrophages, Peritoneal, Mice, Mice, Knockout, Nitric Oxide, Phagocytosis, Survival Rate, T-Lymphocytes
Show Abstract · Added May 4, 2017
5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung. The fungal susceptibility of 5-LO(-/-) mice correlated with a lower rate of macrophage ingestion of IgG-H. capsulatum relative to WT macrophages. Conversely, exogenous LTB4 and LTC4 restored macrophage phagocytosis in 5-LO deficient mice. Our results demonstrate that leukotrienes are required to control chronic fungal infection by amplifying both the innate and adaptive immune response during histoplasmosis.
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21 MeSH Terms
Organ-specific features of natural killer cells.
Shi FD, Ljunggren HG, La Cava A, Van Kaer L
(2011) Nat Rev Immunol 11: 658-71
MeSH Terms: Animals, Autoimmunity, Brain, Cell Communication, Cytokines, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Humans, Inflammation, Intestinal Mucosa, Joints, Killer Cells, Natural, Liver, Mice, Mice, Transgenic, Organ Specificity, Pancreas, Receptors, Antigen, T-Cell, Receptors, Cytokine, Signal Transduction, Uterus
Show Abstract · Added March 20, 2014
Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells.
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22 MeSH Terms
Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology.
Hao J, Liu R, Piao W, Zhou Q, Vollmer TL, Campagnolo DI, Xiang R, La Cava A, Van Kaer L, Shi FD
(2010) J Exp Med 207: 1907-21
MeSH Terms: Animals, Autoimmunity, Cell Movement, Cells, Cultured, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Immune Tolerance, Interleukin-17, Interleukin-2, Killer Cells, Natural, Mice, Mice, Knockout, Multiple Sclerosis, T-Lymphocytes, Helper-Inducer
Show Abstract · Added December 10, 2013
Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention.
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15 MeSH Terms