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Immune Checkpoint and Other Receptor-Ligand Pairs Modulating Macrophages in Cancer: Present and Prospects. Cancers (Basel) 2022; 14:cancers14235963. [PMID: 36497444 PMCID: PMC9736575 DOI: 10.3390/cancers14235963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/26/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Immunotherapy, especially immune checkpoint blocking, has become the primary anti-tumor treatment in recent years. However, the current immune checkpoint inhibitor (ICI) therapy is far from satisfactory. Macrophages are a key component of anti-tumor immunity as they are a common immune cell subset in tumor tissues and act as a link between innate and adaptive immunity. Hence, understanding the regulation of macrophage activation in tumor tissues by receptor-ligand interaction will provide promising macrophage-targeting strategies to complement current adaptive immunity-based immunotherapy and traditional anti-tumor treatment. This review aims to offer a systematic summary of the current advances in number, structure, expression, biological function, and interplay of immune checkpoint and other receptor-ligand between macrophages and tumor cells.
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Liang S, Lin X, Liang Y, Song D, Zhang L, Fan X. Killing Effects of IFN R -/- Mouse NK Cells Activated by HN Protein of NDV on Mouse Hepatoma Cells and Possible Mechanism with Syk and NF-κB. Anat Rec (Hoboken) 2019; 302:1718-1725. [PMID: 31120191 PMCID: PMC6771794 DOI: 10.1002/ar.24177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/27/2018] [Accepted: 12/08/2018] [Indexed: 11/07/2022]
Abstract
The objective of this article is to evaluate whether the tumoricidal activity of mouse IFN R-/- nature killer (NK) cells is induced by Newcastle disease virus hemagglutinin-neuraminidase (NDV-HN) stimulation, and to investigate what is the mechanism of the HN-stimulated NK cells to kill mouse hepatoma cell line in vitro. The mouse IFN R-/- NK cells were stimulated for 16 hr with 500 ng/mL NDV-HN in 1640 medium. Quantify the cytotoxic activities of NK cells against mouse hepatoma cells (Hepa1-6) by flow cytometry. Granzymes B (GrB) and Fas/FasL concentrations in the supernatants of IFN R-/- NK cells medium were determined by specific ELISA assay. The expression of cell surface GrB and Fas was determined by Western blot. NDV-HN stimulation enhanced tumoricidal activity of IFN R-/- NK cells toward Hepa1-6 in vitro. Treating with anti-HN neutralizing mAb induced significant decline in the cytotoxicity of IFN R-/- NK cells toward Hepa1-6 cell line (P < 0.05). After treating with anti-HN protein (1 μL/mL), Syk-specific inhibitor Herbimycin A(250 ng/mL) and NF-κB inhibitor PDTC (500 ng/mL) downregulated the tumoricidal activity of HN-stimulated IFN R-/- NK cells (P < 0.05). Moreover, significant suppressions in the production of GrB and Fas/FasL were observed in HN-stimulated IFN R-/- NK cells (P < 0.05). Thus, we concluded that killer activation receptors pathway is involved in the IFN-γ-independent GrB and Fas/FasL expression of NDV-HN-stimulated IFN R-/- NK cells, and these are activated by Syk and NF-κB. Anat Rec, 302:1718-1725, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association for Anatomy.
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Affiliation(s)
- Shuang Liang
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
- Department of Pharmaceutical and Medical EquipmentTrading Center of Guangxi Public ResourcesNanningGuangxiChina
| | - Xiao Lin
- Guangxi Key Laboratory of Traditional Chinese Medicine Quality StandardsGuangxi Institute of Traditional Medical and Pharmaceutical SciencesNanningChina
| | - Ying Liang
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
| | - Dezhi Song
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
| | - Lei Zhang
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
| | - Xiaohui Fan
- Department of MicrobiologyThe School of Preclinical Medicine, Guangxi Medical UniversityNanningGuangxiChina
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Cubero FJ, Woitok MM, Zoubek ME, de Bruin A, Hatting M, Trautwein C. Disruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease. Cell Death Dis 2019; 10:115. [PMID: 30737368 PMCID: PMC6368573 DOI: 10.1038/s41419-019-1391-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/16/2019] [Accepted: 01/21/2019] [Indexed: 12/21/2022]
Abstract
Fas Ligand (FasL) and Fas (APO-1/CD95) are members of the TNFR superfamily and may trigger apoptosis. Here, we aimed to elucidate the functional role of Fas signaling in an experimental model of chronic liver disease, the hepatocyte-specific NEMO knockout (NEMOΔhepa) mice. We generated NEMOΔhepa /Faslpr mice, while NEMOΔhepa, NEMOf/f as well as Faslpranimals were used as controls, and characterized their phenotype during liver disease progression. Liver damage was evaluated by serum transaminases, histological, immunofluorescence procedures, and biochemical and molecular biology techniques. Proteins were detected by western Blot, expression of mRNA by RT-PCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Faslpr mutation in NEMOΔhepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMOΔhepa mice. Moreover, NEMOΔhepa/Faslpr animals elicited significantly decreased parameters of liver fibrosis, such as Collagen IA1, MMP2, and TIMP1, and reduced proinflammatory macrophages and cytokine expression. At 52 weeks of age, NEMOΔhepa/Faslpr exhibited less malignant growth as evidenced by reduced HCC burden associated with a significantly decreased number of nodules and LW/BW ratio and decreased myeloid populations. Deletion of TNFR1 further reduced tumor load of 52-weeks-old NEMOΔhepa/Faslpr mice. The functionality of FasL/Fas might affect inflammation-driven tumorigenesis in an experimental model of chronic liver disease. These results help to develop alternative therapeutic approaches and extend the limitations of tumor therapy against HCC.
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Affiliation(s)
- Francisco Javier Cubero
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany. .,Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain. .,12 de Octubre Health Research Institute (imas12), Madrid, Spain.
| | | | - Miguel E Zoubek
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.,Department of Toxicology, Faculty of Health Medicine and Life Sciences, School of Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
| | - Alain de Bruin
- Department of Toxicology, Faculty of Health Medicine and Life Sciences, School of Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands.,Institute of Pathology, Utrecht University, Utrecht, The Netherlands
| | - Maximilian Hatting
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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Goebeler ME, Bargou R. Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy. Leuk Lymphoma 2016; 57:1021-32. [DOI: 10.3109/10428194.2016.1161185] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Rozhkova AV, Zinovyeva MV, Sass AV, Zborovskaya IB, Limborska SA, Dergunova LV. Expression of sphingomyelin synthase 1 (SGMS1) gene varies in human lung and esophagus cancer. Mol Biol 2014. [DOI: 10.1134/s0026893314030170] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Hofmanová J, Straková N, Vaculová AH, Tylichová Z, Šafaříková B, Skender B, Kozubík A. Interaction of dietary fatty acids with tumour necrosis factor family cytokines during colon inflammation and cancer. Mediators Inflamm 2014; 2014:848632. [PMID: 24876678 PMCID: PMC4021685 DOI: 10.1155/2014/848632] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 03/29/2014] [Indexed: 12/14/2022] Open
Abstract
Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF- α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NF κ B activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.
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Affiliation(s)
- Jiřina Hofmanová
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
| | - Nicol Straková
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
| | - Alena Hyršlová Vaculová
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
| | - Zuzana Tylichová
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
- Institute of Experimental Biology, Department of Animal Physiology and Immunology, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
| | - Barbora Šafaříková
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
- Institute of Experimental Biology, Department of Animal Physiology and Immunology, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
| | - Belma Skender
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
| | - Alois Kozubík
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic
- Institute of Experimental Biology, Department of Animal Physiology and Immunology, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
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Abrams SI. A multi-functional role of interferon regulatory factor-8 in solid tumor and myeloid cell biology. Immunol Res 2010; 46:59-71. [PMID: 19756408 DOI: 10.1007/s12026-009-8125-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Understanding mechanisms of tumor escape are critically important not only to improving our knowledge of cancer biology, but also for the overall development of more effective anti-neoplastic therapies. Our laboratory focuses on mechanisms of apoptotic resistance, with emphasis on Fas loss of function as an important determinant of tumor progression. Our work in solid tumor systems has led to the identification of interferon regulatory factor-8 (IRF-8) as a differentially expressed gene important for tumor cell response to cytotoxicity, including Fas-mediated apoptosis and host-anti-tumor immunosurveillance mechanisms. Although IRF-8 was originally identified in the regulation of normal and neoplastic myeloid cell development, these findings revealed a new functional role for IRF-8 in non-hematopoietic malignancies and establish a molecular basis for its potential manipulation during cancer therapy.
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Affiliation(s)
- Scott I Abrams
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
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[Dissecting the pathways of tumour escape: " question of life and death?"]. An Bras Dermatol 2010; 85:248-59. [PMID: 20520947 DOI: 10.1590/s0365-05962010000200022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Accepted: 12/15/2009] [Indexed: 11/22/2022] Open
Abstract
Apoptotic pathways are providing important saveguard mechanisms in protection from cancer by eliminating altered and often harmful cells. The disturbances of cell proliferation, differentiation and apoptosis are also found on specific signal-transduction pathways within the tumour cells and between these and the immune system. The article focuses attention on the evolution of the melanocytic naevi in the direction of a dysplastic or tumour cell. The determination of single molecules as prognostic parameters within cancer genesis seems to be problematic. New hopes are being placed on the treatment with TW-37, ABT-737 and TAT-Bim, which, to an extent, are able to support the programmed cell death. The clinical importance of these innovative therapies remains to be seen and should therefore, be viewed with considerable criticism.
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Cierniewski CS, Papiewska-Pajak I, Malinowski M, Sacewicz-Hofman I, Wiktorska M, Kryczka J, Wysocki T, Niewiarowska J, Bednarek R. Thymosin β4 regulates migration of colon cancer cells by a pathway involving interaction with Ku80. Ann N Y Acad Sci 2010; 1194:60-71. [PMID: 20536451 DOI: 10.1111/j.1749-6632.2010.05480.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Zhang HY, Li JY, Zhang JY. Effect of Fas, FasL and Caspase-3 on apoptosis of retinoic acid-induced gastric carcinoma cells. Shijie Huaren Xiaohua Zazhi 2008; 16:3255-3260. [DOI: 10.11569/wcjd.v16.i29.3255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect on apoptosis of retinoic acid (RA)-induced BGC-803 gastric carcinoma cells and its relationship with the expression of Fas, FasL and Caspase-3.
METHODS: BGC-803 cells were treated with different concentrations of RA (0.001, 0.01, 0.1, 1, 10, 20 μmol/L) for 72 h. Then methyl-tetrazolium (MTT) assay was performed to determine the growth inhibition of BGC-803 cells; cell apoptosis rate was determined using flow cytometry; the feature of cell apoptosis was observed by Hoechst33342/PI staining; the mRNA expression of Fas, FasL and Caspase-3 were estimated using reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: After BGC-803 cells were treated with RA (0.1-20 μmol/L) for 72 h, RA inhibited the growth of cells significantly compared with that in the control group (32.61%, 44.42%, 48.14%, 51.15% vs 0.657%; all P < 0.01). Cells in G2/M were significantly increased after the cells were treated with 20 μmol/L RA for 12 h, 24 h and 48 h. G1 peak specific to apoptosis was observed and also observed were chromatic agglutination and rupture of caryon membrane. Expressions of Fas, FasL and Caspase-3 mRNA were up-regulated significantly by RA for 48 h compared with that in the control group.
CONCLUSION: Fas, FasL and Caspase-3 are involved in gastric carcinoma cell apoptosis induced by RA.
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11
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Boutros T, Chevet E, Metrakos P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev 2008; 60:261-310. [PMID: 18922965 DOI: 10.1124/pr.107.00106] [Citation(s) in RCA: 450] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Mitogen-activated protein kinase dual-specificity phosphatase-1 (also called MKP-1, DUSP1, ERP, CL100, HVH1, PTPN10, and 3CH134) is a member of the threonine-tyrosine dual-specificity phosphatases, one of more than 100 protein tyrosine phosphatases. It was first identified approximately 20 years ago, and since that time extensive investigations into both mkp-1 mRNA and protein regulation and function in different cells, tissues, and organs have been conducted. However, no general review on the topic of MKP-1 exists. As the subject matter pertaining to MKP-1 encompasses many branches of the biomedical field, we focus on the role of this protein in cancer development and progression, highlighting the potential role of the mitogen-activated protein kinase (MAPK) family. Section II of this article elucidates the MAPK family cross-talk. Section III reviews the structure of the mkp-1 encoding gene, and the known mechanisms regulating the expression and activity of the protein. Section IV is an overview of the MAPK-specific dual-specificity phosphatases and their role in cancer. In sections V and VI, mkp-1 mRNA and protein are examined in relation to cancer biology, therapeutics, and clinical studies, including a discussion of the potential role of the MAPK family. We conclude by proposing an integrated scheme for MKP-1 and MAPK in cancer.
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Affiliation(s)
- Tarek Boutros
- Department of Surgery, Royal Victoria Hospital, McGill University, 687 Pine Ave. W., Montreal, QC H3A1A1, Canada.
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Neeley YC, Arredouani MS, Hollenbeck B, Eng MH, Rubin MA, Sanda MG. Partially circumventing peripheral tolerance for oncogene-specific prostate cancer immunotherapy. Prostate 2008; 68:715-27. [PMID: 18302222 DOI: 10.1002/pros.20689] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Failure of cancer immunotherapy is essentially due to immunological tolerance to tumor-associated antigens (TAAs), as these antigens are also expressed in healthy tissues. METHODS Here, we used transgenic adenocarcinoma of mouse prostate (TRAMP) mice, which develop lethal prostate cancer due to prostate-specific expression of SV40 T antigen (Tag), to evaluate effects of prostatic transformation on oncogene TAA-specific tolerance and to test the possibility of breaking such tolerance using a modified recombinant vaccinia virus. RESULTS We showed that Tag expression in TRAMP mice is uniquely extra-thymic, and levels of prostatic Tag expression positively correlate with malignant transformation of the prostate. Yet, young tumor-free TRAMP mice were tolerant to Tag antigen. We therefore attempted overcoming such peripheral oncogene-specific T cell tolerance through immunization with a vaccinia construct encoding Tag immunogenic epitopes. This vaccination modality showed that oncogene-specific tolerance was successfully overcome by effective in vivo priming of Tag-specific cytotoxic T cells (CTLs). However, this was restricted to young TRAMP mice. Tag-specific CTL from "tumor naïve" young TRAMP mice showed significant anti-tumor efficacy in vivo by eliminating established heterotopic prostate tumors and prolonging survival in SCID mice harboring Tag-expressing tumors. In contrast, older TRAMP mice with established prostate tumors exhibited oncogene-specific tolerance as evidenced by failure to generate Tag-specific CTL following Tag-specific immunization. CONCLUSIONS Peripheral tolerance can be overcome for effective anti-tumor therapy following oncogene-specific immunization. However, this ability to elicit oncogene-specific CTL is impeded in the tumor-bearing host, in the context of increased oncogene expression associated with tumor progression.
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Affiliation(s)
- Yilin C Neeley
- Department of Urology, Surgery, and Pathology, University of Michigan. Ann Arbor, Michigan, USA
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Mao H, Liu Q, Zhang J, Gu H, Wang L, Zhou X, Yin H, Zhang L, Xie F, Jiang G. Effects of specific antisense oligonucleotide inhibition of Fas expression on T cell apoptosis induced by Fas ligand. Int Immunopharmacol 2007; 7:1714-22. [PMID: 17996681 DOI: 10.1016/j.intimp.2007.09.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2007] [Revised: 08/21/2007] [Accepted: 09/05/2007] [Indexed: 01/15/2023]
Abstract
To investigate the effect of specific antisense oligodeoxynucleotide (ASODN) inhibition of Fas expression on T cell apoptosis induced by hepatocarcinoma cells. Fas receptor (Fas) and Fas ligand (FasL) expressed by the hepatocarcinoma cell line HepG2.2.15 and Jurkat T cells were detected by flow cytometry (FCM) and the ability of FasL-inducing T cell apoptosis was tested by co-culture assay in vitro with HepG2.2.15 cells and Jurkat T cells. The Jurkat cells were transfected with Fas-ASODN using lipofectin, and the effects of Fas-ASODN on Fas mRNA level, Fas expression on T cells surface, and apoptosis were investigated by RT-PCR, FCM and co-culture assay, respectively. It was found that HepG2.2.15 cells expressing functional FasL could induce the apoptosis of Jurkat cells as demonstrated by co-culture assays. After the Jurkat cells were transfected with Fas ASODN, the level of Fas mRNA, the expression rate of Fas and the apoptotic rate induced by hepatocarcinoma cells were all decreased. As a conclusion, it is evident that hepatocarcinoma cells expressing FasL can induce apoptosis in Fas-expressing T cells, indicating that transfection of Fas ASODN can partially convert the immune inhibitory condition induced by hepatocarcinoma cells.
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Affiliation(s)
- Haiting Mao
- Institute of Immunology, Shandong University School of Medicine, Jinan, 250012, People's Republic of China.
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Brandl C, Haas C, d’Argouges S, Fisch T, Kufer P, Brischwein K, Prang N, Bargou R, Suzich J, Baeuerle PA, Hofmeister R. The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Immunother 2007; 56:1551-63. [PMID: 17310380 PMCID: PMC11030660 DOI: 10.1007/s00262-007-0298-z] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2006] [Accepted: 01/27/2007] [Indexed: 12/30/2022]
Abstract
BiTE molecules comprise a new class of bispecific single-chain antibodies redirecting previously unstimulated CD8+ and CD4+ T cells for the elimination of target cells. One example is MT103 (MEDI-538; bscCD19xCD3), a CD19-specific BiTE that can induce lysis of normal and malignant B cells at low picomolar concentrations, which is accompanied by T cell activation. Here, we explored in cell culture the impact of the glucocorticoid derivative dexamethasone on various activation parameters of human T cells in response to MT103. In case cytokine-related side effects should occur with BiTE molecules and other T cell-based approaches during cancer therapy it is important to understand whether glucocorticoids do interfere with the cytotoxic potential of T cells. We found that MT103 induced in the presence of target cells secretion by peripheral T cells of interleukin (IL)-2, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-6, IL-10 and IL-4 into the cell culture medium. Production of all studied cytokines was effectively reduced by dexamethasone at a concentration between 1 and 3x10(-7) M. In contrast, upregulation of activation markers CD69, CD25, CD2 and LFA-1 on both CD4+ and CD8+ T cells, and T cell proliferation were barely affected by the steroid hormone analogue. Most importantly, dexamethasone did not detectably inhibit the cytotoxic activity of MT103-activated T cells against a human B lymphoma line as investigated with lymphocytes from 12 human donors. Glucocorticoids thus qualify as a potential co-medication for therapeutic BiTE molecules and other cytotoxic T cell therapies for treatment of cancer.
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Affiliation(s)
| | - Cornelia Haas
- Micromet AG, Staffelseestr. 2, 814777 Munich, Germany
| | | | - Tanja Fisch
- Micromet AG, Staffelseestr. 2, 814777 Munich, Germany
| | - Peter Kufer
- Micromet AG, Staffelseestr. 2, 814777 Munich, Germany
| | | | - Nadja Prang
- Micromet AG, Staffelseestr. 2, 814777 Munich, Germany
- Present Address: Serono International SA, Via di Valle Caia 22, 00040 Ardea, Italy
| | - Ralf Bargou
- University Clinic, Klinikstrasse 6-8, 97070 Wuerzburg, Germany
| | - JoAnn Suzich
- Medimmune Inc., One Medimmune Way, Gaithersburg, MD USA
| | | | - Robert Hofmeister
- Micromet AG, Staffelseestr. 2, 814777 Munich, Germany
- Present Address: Serono Research Institute, Inc., One Technology Place, Rockland, MA 02370 USA
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15
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Kruzelock RP, Short W. Colorectal Cancer Therapeutics and the Challenges of Applied Pharmacogenomics. Curr Probl Cancer 2007; 31:315-66. [PMID: 17905192 DOI: 10.1016/j.currproblcancer.2007.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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16
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de Oliveira GM, Diniz RL, Batista W, Batista MM, Bani Correa C, de Araújo-Jorge TC, Henriques-Pons A. Fas ligand-dependent inflammatory regulation in acute myocarditis induced by Trypanosoma cruzi infection. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 171:79-86. [PMID: 17591955 PMCID: PMC1941608 DOI: 10.2353/ajpath.2007.060643] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Fas/Fas ligand (Fas-L) engagement, a potent inducer of apoptosis, is also important for cellular activation, regulation of effector and chemotactic activity, and secretion of chemokines and cytokines. We evaluated the relevance of Fas/Fas-L in the regulation of myocarditis induced by Trypanosoma cruzi infection and observed that in Fas-L(-/-) mice (gld/gld), cardiac infiltration was significantly reduced, accordingly showing less cardiomyocyte destruction. Fluorescence-activated cell sorting analysis of cardiac inflammatory cells showed higher numbers of CD8(+) T cells in BALB/c compared with gld/gld mice but similar levels of lymphocyte function-associated antigen-1, intercellular adhesion molecule, CD2, and CD69 expression; MAC-1(+) myeloid cells and mast cells were increased in BALB/c mice, whereas gld/gld mice exhibited an enrichment of CD4(+/low) T cells. Intracellular labeling of cytokines revealed no clear cardiac skewing of Th1 or Th2 responses, but we found a higher number of interleukin-10(+) cells in gld/gld mice and a deficient expression of vascular cell adhesion molecule-1 on cardiac endothelial cells in gld/gld mice. Finally, we found a population of CD3(+) but CD4/CD8 double negative cardiac T cells in both groups of infected mice, but down-regulation of some adhesion molecules and surface receptors was only observed in gld/gld mice, indicating a targeted T-cell population mostly affected by the lack of Fas-L engagement. These results point to a role for myocarditis regulation by Fas/Fas-L beyond its possible direct relevance in cellular death.
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Affiliation(s)
- Gabriel Melo de Oliveira
- Fundação Oswaldo Cruz/Instituto Oswaldo Cruz, Departamento de Ultra-estrutura e Biologia Celular (DUBC), Laboratório de Biologia Celular, Rio de Janeiro (RJ); Brazil
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Miller AM, Pisa P. Tumor escape mechanisms in prostate cancer. Cancer Immunol Immunother 2007; 56:81-7. [PMID: 16362411 PMCID: PMC11041923 DOI: 10.1007/s00262-005-0110-x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2005] [Accepted: 11/25/2005] [Indexed: 10/25/2022]
Abstract
Numerous immunotherapy trials have been carried out in prostate cancer (PC) patients, with induction of antigen-specific T cells in some cases. Despite this capability, limited success is seen in terms of tumor regression or survival. In this review, we discuss the evidence for tumor escape strategies that may contribute to vaccine failure in the setting of PC. These include defects in antigen presentation, production of immunosuppressive substances, induction of T cell death, T cell receptor dysfunction, and the presence of tolerogenic dendritic cells and regulatory T cells inside prostate tumors. It is clear that novel strategies aimed at preventing tumor escape, such as small molecular weight inhibitors of immunosuppressive molecules, adoptive transfer of TCR transgenic T cells, removal of Tregs, combined with anti-androgen therapy and prostate-specific vaccines, need to be examined further in PC patients.
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Affiliation(s)
- Ashley M Miller
- Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska Institute, 171 76, Stockholm, Sweden.
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Young MRI. Protective mechanisms of head and neck squamous cell carcinomas from immune assault. Head Neck 2006; 28:462-70. [PMID: 16284974 DOI: 10.1002/hed.20331] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that is the sixth most common neoplasm in the world. Despite advances in treatments involving surgery, radiation, and chemotherapy, the 5-year survival has remained at less than 50% for the past 30 years, primarily because of local recurrences. Thus, the possibility of immunotherapeutic approaches for patients with HNSCC has gained interest. Unfortunately, patients with HNSCC have profound immune defects that are associated with increased recurrence. This review aims to provide an overview of both the defensive and immune subversive mechanisms by which patients with HNSCC can protect themselves from immune antitumor assault.
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Affiliation(s)
- M Rita I Young
- Research Services, Research Service (151), Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401-5799, USA.
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Egorov IK. Mouse models of efficient and inefficient anti-tumor immunity, with emphasis on minimal residual disease and tumor escape. Cancer Immunol Immunother 2006; 55:1-22. [PMID: 16091932 PMCID: PMC11030122 DOI: 10.1007/s00262-005-0007-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Accepted: 03/25/2005] [Indexed: 10/25/2022]
Abstract
Tumor escape from the host immune response remains the major problem holding the development of immunotherapies for cancer. In this review, congenic mouse lines are discussed that differ dramatically in their ability to respond to tumors tested and, thereby, to survive or to succumb to the tumor and/or its metastases. This ability is under the control of either MHC class I or nontrivial MHC class II beta genes expressed in a small subpopulation of antigen-presenting cells. Two hypotheses can explain the results obtained so far: (1) emergence of tumor cell variants that escape the host immune response in morbid mice but are eliminated in survivors, and (2) tumor-induced immunosuppression, which is either efficient or not, depending on the congenic line used. It is argued that further experimentation on these congenics will allow to choose the correct hypothesis, and to characterize the mechanism(s) of elimination of minimal residual disease and prevention of tumor escape by the immune system of survivors as well as the reason(s) for its failure in morbid mice. It is also argued that the use of these models will substantially increase the chance to resolve the controversy of poor correlation of immunotherapy testing in mice with clinical results.
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Affiliation(s)
- Igor K Egorov
- The Jackson Laboratory, Bar Harbor, ME 04609-1500, USA,
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Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discov Today 2005; 10:1237-44. [PMID: 16213416 DOI: 10.1016/s1359-6446(05)03554-3] [Citation(s) in RCA: 196] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Bispecific T-cell engager molecules (BiTEs) constitute a class of bispecific single-chain antibodies for the polyclonal activation and redirection of cytotoxic T cells against pathogenic target cells. BiTEs combine a unique set of properties that have not yet been reported for any other kind of bispecific antibody construct, namely extraordinary potency and efficacy against target cells at low T-cell numbers without the need for T-cell co-stimulation. Here we review novel insights into the mechanism of BiTE action, which help to explain the unique features of BiTEs, as well as data from various animal models demonstrating the outstanding therapeutic potential of BiTEs for the treatment of malignant diseases.
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Affiliation(s)
- Evelyn Wolf
- Micromet AG, Staffelseestr. 2, 81477 Munich, Germany
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Zhu Q, Liu JY, Xu HW, Yang CM, Zhang AZ, Cui Y, Wang HB. Mechanism of counterattack of colorectal cancer cell by Fas/Fas ligand system. World J Gastroenterol 2005; 11:6125-9. [PMID: 16273638 PMCID: PMC4436628 DOI: 10.3748/wjg.v11.i39.6125] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the role of Fas/Fas ligand (FasL) in the immune escape of colon cancer cells.
METHODS: Immunohistochemistry was used to observe the expression of Fas and FasL in the tissues of colon cancer patients.In situ hybridization was used to detect the localization of FasL mRNA expression in cancer tissues. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay and CD45 staining were performed to detect the apoptosis of tumor-infiltrating lymphocytes (TILs). Co-culture assays of colon cancer cells (SW480) and Jurkat cells (Fas-sensitive cells) were performed to observe the counterattack of colon cancer cells to lymphocytes.
RESULTS: Of 53 cases of colon carcinomas, 23 cases (43.4%) expressed Fas which was significantly lower as compared to the normal colonic mucosa (73.3%, P<0.01), and 45 cases (84.9%) of colon carcinomas expressed FasL, whereas only two cases (3.75%) in normal mucosa expressed FasL. FasL expression in the colon cancer cells was found to be associated with increased cell death of TILs. The apoptotic rate of TIL in the FasL-positive staining regions of tumor cells was significantly higher than that in the FasL-negative staining region (54.84 ± 2.79% vs 25.73 ± 1.98%, P<0.01). The co-culture of SW480 cells and Jurkat cells confirmed the function of FasL on the SW480 cells. The apoptotic rates of Jurkat cells were found to be related with the amount of SW480 cells.
CONCLUSION: Colon cancer cells can escape the immune surveillance and killing via decreasing Fas expression, and can counterattack the immune system via increasing FasL expression. Fas/FasL can serve as potential targets for effective antitumor therapy.
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Affiliation(s)
- Qiang Zhu
- Department of Gastroenterology, Shandong Provincial Hospital, Jing 5 Wei 7 Road, 324#, Jinan 250021, Shandong Province, China.
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