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You H, Song S, Liu D, Ren T, Yin SJ, Wu P, Mao J. Mechanism of Wenshen Xuanbi Decoction in the treatment of osteoarthritis based on network pharmacology and experimental verification. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2024; 28:59-72. [PMID: 38154965 PMCID: PMC10762491 DOI: 10.4196/kjpp.2024.28.1.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/07/2023] [Accepted: 11/14/2023] [Indexed: 12/30/2023]
Abstract
To investigate the mechanism of Wenshen Xuanbi Decoction (WSXB) in treating osteoarthritis (OA) via network pharmacology, bioinformatics analysis, and experimental verification. The active components and prediction targets of WSXB were obtained from the TCMSP database and Swiss Target Prediction website, respectively. OA-related genes were retrieved from GeneCards and OMIM databases. Protein-protein interaction and functional enrichment analyses were performed, resulting in the construction of the Herb-Component-Target network. In addition, differential genes of OA were obtained from the GEO database to verify the potential mechanism of WSXB in OA treatment. Subsequently, potential active components were subjected to molecular verification with the hub targets. Finally, we selected the most crucial hub targets and pathways for experimental verification in vitro. The active components in the study included quercetin, linolenic acid, methyl linoleate, isobergapten, and beta-sitosterol. AKT1, tumor necrosis factor (TNF), interleukin (IL)-6, GAPDH, and CTNNB1 were identified as the most crucial hub targets. Molecular docking revealed that the active components and hub targets exhibited strong binding energy. Experimental verification demonstrated that the mRNA and protein expression levels of IL-6, IL-17, and TNF in the WSXB group were lower than those in the KOA group (p < 0.05). WSXB exhibits a chondroprotective effect on OA and delays disease progression. The mechanism is potentially related to the suppression of IL-17 and TNF signaling pathways and the down-regulation of IL-6.
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Affiliation(s)
- Hankun You
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
| | - Siyuan Song
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
| | - Deren Liu
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
| | - Tongsen Ren
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
| | - Song Jiang Yin
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
| | - Peng Wu
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
| | - Jun Mao
- Department of Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China
- Department of Orthopedics, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China
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Wu AA, Drake V, Huang HS, Chiu S, Zheng L. Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells. Oncoimmunology 2015; 4:e1016700. [PMID: 26140242 DOI: 10.1080/2162402x.2015.1016700] [Citation(s) in RCA: 202] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/02/2015] [Accepted: 02/03/2015] [Indexed: 02/08/2023] Open
Abstract
It has become evident that tumor-induced immuno-suppressive factors in the tumor microenvironment play a major role in suppressing normal functions of effector T cells. These factors serve as hurdles that limit the therapeutic potential of cancer immunotherapies. This review focuses on illustrating the molecular mechanisms of immunosuppression in the tumor microenvironment, including evasion of T-cell recognition, interference with T-cell trafficking, metabolism, and functions, induction of resistance to T-cell killing, and apoptosis of T cells. A better understanding of these mechanisms may help in the development of strategies to enhance the effectiveness of cancer immunotherapies.
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Key Words
- 1MT, 1-methyltryptophan
- COX2, cyclooxygenase-2
- GM-CSF, granulocyte macrophage colony-stimulating factor
- GPI, glycosylphosphatidylinositol
- Gal1, galectin-1
- HDACi, histone deacetylase inhibitor
- HLA, human leukocyte antigen
- IDO, indoleamine-2,3- dioxygenase
- IL-10, interleukin-10
- IMC, immature myeloid cell
- MDSC, myeloid-derived suppressor cells
- MHC, major histocompatibility
- MICA, MHC class I related molecule A
- MICB, MHC class I related molecule B
- NO, nitric oxide
- PARP, poly ADP-ribose polymerase
- PD-1, program death receptor-1
- PD-L1, programmed death ligand 1
- PGE2, prostaglandin E2
- RCAS1, receptor-binding cancer antigen expressed on Siso cells 1
- RCC, renal cell carcinoma
- SOCS, suppressor of cytokine signaling
- STAT3, signal transducer and activator of transcription 3
- SVV, survivin
- T cells
- TCR, T-cell receptor
- TGF-β, transforming growth factor β
- TRAIL, TNF-related apoptosis-inducing ligand
- VCAM-1, vascular cell adhesion molecule-1
- XIAP, X-linked inhibitor of apoptosis protein
- iNOS, inducible nitric-oxide synthase
- immunosuppression
- immunosuppressive factors
- immunotherapy
- tumor microenvironment
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Affiliation(s)
- Annie A Wu
- Department of Oncology; The Johns Hopkins University School of Medicine ; Baltimore, MD USA
| | - Virginia Drake
- School of Medicine; University of Maryland ; Baltimore, MD USA
| | | | - ShihChi Chiu
- College of Medicine; National Taiwan University ; Taipei, Taiwan
| | - Lei Zheng
- Department of Oncology; The Johns Hopkins University School of Medicine ; Baltimore, MD USA
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Muturi HT, Dreesen JD, Nilewski E, Jastrow H, Giebel B, Ergun S, Singer BB. Tumor and endothelial cell-derived microvesicles carry distinct CEACAMs and influence T-cell behavior. PLoS One 2013; 8:e74654. [PMID: 24040308 PMCID: PMC3770572 DOI: 10.1371/journal.pone.0074654] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 08/08/2013] [Indexed: 01/15/2023] Open
Abstract
Normal and malignant cells release a variety of different vesicles into their extracellular environment. The most prominent vesicles are the microvesicles (MVs, 100-1 000 nm in diameter), which are shed of the plasma membrane, and the exosomes (70-120 nm in diameter), derivates of the endosomal system. MVs have been associated with intercellular communication processes and transport numerous proteins, lipids and RNAs. As essential component of immune-escape mechanisms tumor-derived MVs suppress immune responses. Additionally, tumor-derived MVs have been found to promote metastasis, tumor-stroma interactions and angiogenesis. Since members of the carcinoembryonic antigen related cell adhesion molecule (CEACAM)-family have been associated with similar processes, we studied the distribution and function of CEACAMs in MV fractions of different human epithelial tumor cells and of human and murine endothelial cells. Here we demonstrate that in association to their cell surface phenotype, MVs released from different human epithelial tumor cells contain CEACAM1, CEACAM5 and CEACAM6, while human and murine endothelial cells were positive for CEACAM1 only. Furthermore, MVs derived from CEACAM1 transfected CHO cells carried CEACAM1. In terms of their secretion kinetics, we show that MVs are permanently released in low doses, which are extensively increased upon cellular starvation stress. Although CEACAM1 did not transmit signals into MVs it served as ligand for CEACAM expressing cell types. We gained evidence that CEACAM1-positive MVs significantly increase the CD3 and CD3/CD28-induced T-cell proliferation. All together, our data demonstrate that MV-bound forms of CEACAMs play important roles in intercellular communication processes, which can modulate immune response, tumor progression, metastasis and angiogenesis.
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Affiliation(s)
| | | | - Elena Nilewski
- Institute of Anatomy, University Hospital Essen, Essen, Germany
| | - Holger Jastrow
- Institute of Anatomy, University Hospital Essen, Essen, Germany
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - Suleyman Ergun
- Institute of Anatomy, University Hospital Essen, Essen, Germany
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Bernhard B. Singer
- Institute of Anatomy, University Hospital Essen, Essen, Germany
- * E-mail:
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Matysiak M, Orlowski W, Fortak-Michalska M, Jurewicz A, Selmaj K. Immunoregulatory function of bone marrow mesenchymal stem cells in EAE depends on their differentiation state and secretion of PGE2. J Neuroimmunol 2011; 233:106-11. [DOI: 10.1016/j.jneuroim.2010.12.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Revised: 11/17/2010] [Accepted: 12/10/2010] [Indexed: 12/12/2022]
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Onuma K, Sato Y, Ogawara S, Shirasawa N, Kobayashi M, Yoshitake J, Yoshimura T, Iigo M, Fujii J, Okada F. Nano-scaled particles of titanium dioxide convert benign mouse fibrosarcoma cells into aggressive tumor cells. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 175:2171-83. [PMID: 19815711 DOI: 10.2353/ajpath.2009.080900] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Nanoparticles are prevalent in both commercial and medicinal products; however, the contribution of nanomaterials to carcinogenesis remains unclear. We therefore examined the effects of nano-sized titanium dioxide (TiO(2)) on poorly tumorigenic and nonmetastatic QR-32 fibrosarcoma cells. We found that mice that were cotransplanted subcutaneously with QR-32 cells and nano-sized TiO(2), either uncoated (TiO(2)-1, hydrophilic) or coated with stearic acid (TiO(2)-2, hydrophobic), did not form tumors. However, QR-32 cells became tumorigenic after injection into sites previously implanted with TiO(2)-1, but not TiO(2)-2, and these developing tumors acquired metastatic phenotypes. No differences were observed either histologically or in inflammatory cytokine mRNA expression between TiO(2)-1 and TiO(2)-2 treatments. However, TiO(2)-2, but not TiO(2)-1, generated high levels of reactive oxygen species (ROS) in cell-free conditions. Although both TiO(2)-1 and TiO(2)-2 resulted in intracellular ROS formation, TiO(2)-2 elicited a stronger response, resulting in cytotoxicity to the QR-32 cells. Moreover, TiO(2)-2, but not TiO(2)-1, led to the development of nuclear interstices and multinucleate cells. Cells that survived the TiO(2) toxicity acquired a tumorigenic phenotype. TiO(2)-induced ROS formation and its related cell injury were inhibited by the addition of antioxidant N-acetyl-l-cysteine. These results indicate that nano-sized TiO(2) has the potential to convert benign tumor cells into malignant ones through the generation of ROS in the target cells.
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Affiliation(s)
- Kunishige Onuma
- Department of Biochemistry and Molecular Biology, Yamagata University, Japan
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Fakhrai H, Mantil JC, Liu L, Nicholson GL, Murphy-Satter CS, Ruppert J, Shawler DL. Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 2006; 13:1052-60. [PMID: 16826191 DOI: 10.1038/sj.cgt.7700975] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-beta2 (TGF-beta2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-beta in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 x 10(6)-2 x 10(7) autologous tumor cells per injection. TGF-beta2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-beta antisense-modified tumor cells.
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Affiliation(s)
- H Fakhrai
- Advanced Biotherapies, Inc., San Diego, CA, USA
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Abstract
Several lines of evidence from recent years support the existence of cancer immunosurveillance, especially studies of natural killer (NK) cells and the IFN-gamma pathway. However, immune suppression is clearly observed in cancer patients and tumor-bearing animals as well. The fact is that although cancers often elicit a vigorous immune response during the early part of their growth, the immune response is soon down-regulated, permitting progressive tumor growth. Apparently, the intrinsic plasticity of tumors allows the immune system to sculpt the immunogenic phenotypes of tumors to escape efficient immune destruction. But most evidently, several mechanisms have now been found to contribute to the failure of immune control of tumor growth. Tumor cells have a very low level of MHC class II, costimulatory molecules, and weak antigens. They also produce immune suppressive factors (VEGF, IL-10, PGE(2)) that exert systemic effects on immune cell function. In particular, disabled dendritic cell differentiation, maturation, migration, and function are fundamental to this defect, as they are the most potent antigen-presenting cells (APCs) of the immune system, interacting with T and B lymphocyte as well as NK cells to induce and modulate immune responses. In addition, tumors also alter host hematopoiesis and produce large numbers of immature dendritic cells, and evidence shows that these cells are directly immune suppressive. Harnessing the immune system for effective cancer therapy has remained a great challenge. DC-based vaccines, or DC-based vaccines in combination with treatments designed to improve the host immune environment, may offer hope for more effective cancer immunotherapy. Tumor-host interactions are an important determinant of tumor behavior and response to therapy. How tumors interact with their hosts is thus a very broad and complex topic. In this chapter, we will focus on tumor-host immune interactions and the roles of dendritic cell dysfunction in tumor avoidance of host immune responses. We will survey recent findings regarding tumor immune surveillance, antitumor host immune responses, and how the immune system also functions to promote or select tumor variants with reduced immunogenicity. We will then discuss immune suppression caused by tumors, which is clearly observed in tumor-bearing animals and cancer patients. Finally, we will discuss altered dendritic cell function and differentiation in some detail, as it is likely to be one of the most fundamental mechanisms by which tumors escape immune responses.
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Affiliation(s)
- Li Yang
- Vanderbilt University School of Medicine, Department of Cancer Biology, The Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA
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Cools-Lartigue J, Marshall JC, Caissie AL, Saraiva VS, Burnier MN. Secretion of interleukin-6 and prostaglandin E2 during uveal melanoma-monocyte in vitro interactions. Exp Eye Res 2004; 79:451-4. [PMID: 15381029 DOI: 10.1016/j.exer.2004.05.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2004] [Accepted: 05/19/2004] [Indexed: 10/26/2022]
Abstract
Host-tumor interactions in uveal melanoma are not well understood. It is believed that the cytokine interleukin-6 and the lipid mediator autacoid prostaglandin E2 are involved in tumor growth, proliferation, tumor cell survival, and angiogenesis. These cytokines have been shown to be poor prognostic markers in uveal and cutaneous melanoma. In this study, we investigated the levels of interleukin-6 and prostaglandin E2 in monocyte and uveal melanoma conditioned medium. Five human uveal melanoma cell lines (92.1, MKT-BR, OCM-1, SP6.5 and UW-1), and one monocyte cell line (28SC) were seeded in 6 well plates at a concentration of 1 x 10(6)cells ml(-1). After 18 hr melanoma conditioned medium was placed on the monocyte cell line and monocyte conditioned medium was placed on each uveal melanoma cell line. Tumor cells and monocytes incubated in fresh medium after 18 hr were used as controls. Interleukin-6 and prostaglandin E2 levels were determined by immunoassays prior to media transfer and 6, 12, 24, and 36 hr thereafter. In the absence of conditioned medium, neither product showed baseline levels of expression. Interleukin-6 but not prostaglandin E2, which remained undetectable for the duration of the study, showed up-regulation of expression after incubation in conditioned medium. 28SC incubated in melanoma conditioned medium expressed higher levels of interleukin-6 than did uveal melanoma cells incubated in monocyte conditioned medium. In addition each cell line exhibited a distinct pattern of expression with individual cell lines exhibiting peak levels of cytokine production at different time points. The results of this study offer insight into the mechanism by which interleukin 6 may be involved in tumor-host interactions potentially favoring tumor growth, survival, and proliferation.
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Csiszár A, Szentes T, Haraszti B, Balázs A, Petrányi GG, Pócsik E. The pattern of cytokine gene expression in human colorectal carcinoma. Pathol Oncol Res 2004; 10:109-16. [PMID: 15188028 DOI: 10.1007/bf02893465] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2004] [Accepted: 05/12/2004] [Indexed: 12/13/2022]
Abstract
Systemic and local cytokine environment may modulate the immunogenicity of colorectal cancer cells, and affect anti-tumor immune functions of tumor-infiltrating lymphocytes. We therefore investigated cytokine mRNA expression patterns in tumors and peripheral blood mononuclear cells (PBMC) from patients with colorectal adenocarcinoma. IL-2, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), IL-4, IL-6, IL-8, IL-10 and IL-1 beta mRNAs in single cell suspension of freshly isolated colorectal cancer tissue were studied by RT-PCR. Frequencies of cytokine gene expression were compared to those in normal colonic mucosa from tumor patients. The frequencies of IL-2, IFN-gamma, IL-4 and IL-10 gene expression were also determined in peripheral blood mononuclear cells from patients with colorectal adenocarcinoma and compared to those of healthy individuals. Tumor samples were more frequently positive for IFN-gamma, IL-2, TNF-alpha and IL-10 gene expression than normal mucosa (p=0.0001, p=0.0118, p=0.001 and p<0.0001, respectively). Frequencies of IL-2 and TNF-alpha gene expressions were significantly higher in tumors with a diameter <5 cm, than in those with a diameter >5 cm. The genes for IL-6, IL-1 beta and IL-8 were commonly expressed in both tumor tissue and normal colonic mucosa. IFN-gamma transcripts were detected in more PBMC samples from patients with colorectal cancer than those from normal controls (p=0.0449). Thus, colorectal cancer tissue is characterized by a specific pattern of cytokine gene expression. It is likely that multiple interactions between pro- and anti-inflammatory cytokines regulate tumor growth and the functional activity of tumor-infiltrating lymphocytes.
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Affiliation(s)
- Anna Csiszár
- Department of Physiology, New York Medical College, Valhalla, USA
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Lathers DMR, Achille NJ, Young MRI. Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck. Hum Immunol 2003; 64:1160-6. [PMID: 14630398 DOI: 10.1016/j.humimm.2003.08.024] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Levels of cytokines, and in particular those that reflect Th1 or Th2 bias, were measured in the plasma of patients with head and neck squamous cell carcinomas (HNSCC). Compared with plasma cytokine levels of age-matched controls, cytokine levels in HNSCC patients suggested a shift to a Th2 bias as levels of the Th2 cytokines interleukin-4 (IL-4), IL-6, and IL-10 were increased, and levels of the Th1 cytokine interferon-gamma (IFN-gamma) were decreased. However, levels of the Th1 cytokines IL-2 and granulocyte macrophage-colony-stimulating factor (GM-CSF) were increased, which is not consistent with full Th2 skewing. Assessment of cytokine levels in patients with malignancies other than HNSCC demonstrated many similarities to HNSCC patients, but HNSCC patients exhibited a more pronounced increase in GM-CSF levels and a decline in IFN-gamma levels. For most cytokines there was no association between the shifts in cytokine levels in HNSCC patients and either the extent of tumor burden or extent of metastasis. However, patients with large HNSCC tended to be the population that demonstrated increased levels of IL-4 and IL-6. These results suggest skewing toward a Th2 bias in HNSCC patients, with the Th2 shift being incomplete and indicative of the presence, rather than the extent, of malignant disease.
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Affiliation(s)
- Deanne M R Lathers
- Research Service, Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston, SC 29401, USA
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Yang L, Yamagata N, Yadav R, Brandon S, Courtney RL, Morrow JD, Shyr Y, Boothby M, Joyce S, Carbone DP, Breyer RM. Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Invest 2003; 111:727-35. [PMID: 12618527 PMCID: PMC151895 DOI: 10.1172/jci16492] [Citation(s) in RCA: 168] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Prostaglandin E(2) (PGE(2)), a major COX metabolite, plays important roles in several facets of tumor biology. We characterized the contribution of the PGE(2) EP2 receptor to cancer-associated immune deficiency using EP2(-/-) mice. EP2(-/-) mice exhibited significantly attenuated tumor growth and longer survival times when challenged with MC26 or Lewis lung carcinoma cell lines as compared with their wild-type littermates. While no differences in T cell function were observed, PGE(2) suppressed differentiation of DCs from wild-type bone marrow progenitors, whereas EP2-null cells were refractory to this effect. Stimulation of cells in mixed lymphocyte reactions by wild-type DCs was suppressed by treatment with PGE(2), while EP2(-/-)-derived DCs were resistant to this effect. In vivo, DCs, CD4(+), and CD8(+) T cells were significantly more abundant in draining lymph nodes of tumor-bearing EP2(-/-) mice than in tumor-bearing wild-type mice, and a significant antitumor cytotoxic T lymphocyte response could be observed only in the EP2(-/-) animals. Our data demonstrate an important role for the EP2 receptor in PGE(2)-induced inhibition of DC differentiation and function and the diminished antitumor cellular immune responses in vivo.
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Affiliation(s)
- Li Yang
- Department of Medicine, The Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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Zheng N, Ye SL, Sun RX, Zhao Y, Tang ZY. Effects of cryopreservation and phenylacetate on biological characters of adherent LAK cells from patients with hepatocellular carcinoma. World J Gastroenterol 2002; 8:233-6. [PMID: 11925598 PMCID: PMC4658357 DOI: 10.3748/wjg.v8.i2.233] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To improve the preparation of adherent lymphokine-activated killer (A-LAK) cells and to study the effects of cryopreservation and phenylacetate (PA) on biological characters of A-LAK cells.
METHODS: A-LAK cells were obtained from peripheral blood mononuclear cells (PBMCs) of the patients with hepatocellular carcinoma (HCC) by using L-phenylalanine methyl ester (PME) to deplete immunosuppressive monocytes. Proliferative activity of SMMC7721 cell line after treatment with phenylacetate (PA) was observed. A-LAK cells were treated with the supernatant of SMMC7721 cells that had been pretreated with PA. The changes of proliferation, cytotoxicity and phenotype of A-LAK cells were investigated after cryopreservation.
RESULTS: The expansion of A-LAK cells (96.79 ± 69.10 folds on Day 14) was significantly higher than that of non-adherent LAK (NA-LAK) cells (22.77 ± 13.20) as well as conventional LAK cells (4.64 ± 0.91). PA significantly suppressed the growth of SMMC7721 cells, and the inhibitor ratio was 46%. The supernatant of cultured tumor cells intensively suppressed the proliferation and cytotoxicity of A-LAK cells, but the suppressive effect of the supernatant was previously decreased after treatment with PA. Impairments in proliferation and cytotoxicity of A-LAK cells immediately after thawing of cryopreservation and recovery after reincubation with IL-2 were observed. The cytotoxicity of thawed A-LAK cells on Day 5 was significantly higher than that of fresh A-LAK before freezing (54.8% ± 10.2% vs 40.5% ± 6.4%). No significant change in the percentage of lymphocyte subsets was identified in frozen A-LAK cells as compared with that in the fresh control cells.
CONCLUSION: A-LAK cells can be simply prepared by using PME, and showed a synergistic anti-tumor effect with the combination of PA. Cryopreservation can increase the immunoactivities of A-LAK cells from the patients with hepatocellular carcinoma.
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Affiliation(s)
- Ning Zheng
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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Song E, Chen J, Ouyang N, Su F, Wang M, Heemann U. Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer. Br J Cancer 2001; 85:1047-54. [PMID: 11592778 PMCID: PMC2375090 DOI: 10.1054/bjoc.2001.2042] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2001] [Revised: 06/11/2001] [Accepted: 06/14/2001] [Indexed: 01/24/2023] Open
Abstract
Expression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell-cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues (n = 8). In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion.
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Affiliation(s)
- E Song
- Department of Medicine, University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany
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