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Ma M, Xie Y, Liu J, Wu L, Liu Y, Qin X. Biological effects of IL-21 on immune cells and its potential for cancer treatment. Int Immunopharmacol 2024; 126:111154. [PMID: 37977064 DOI: 10.1016/j.intimp.2023.111154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/28/2023] [Accepted: 10/29/2023] [Indexed: 11/19/2023]
Abstract
Interleukin-21 (IL-21), a member of the IL-2 cytokine family, is one of the most important effector and messenger molecules in the immune system. Produced by various immune cells, IL-21 has pleiotropic effects on innate and adaptive immune responses via regulation of natural killer, T, and B cells. An anti-tumor role of IL-21 has also been reported in the literature, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the tumor cell. Anti-tumor effect of IL-21 enhances when combined with other agents that target tumor cells, immune regulatory circuits, or other immune-enhancing molecules. Therefore, understanding the biology of IL-21 in the tumor microenvironment (TME) and reducing its systemic toxic and side effects is crucial to ensure the maximum benefits of anti-tumor treatment strategies. In this review, we provide a comprehensive overview on the biological functions, roles in tumors, and the recent advances in preclinical and clinical research of IL-21 in tumor immunotherapy.
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Affiliation(s)
- Meichen Ma
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuanyuan Xie
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lina Wu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yong Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
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2
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Yang H, Xun Y, Ke C, Tateishi K, You H. Extranodal lymphoma: pathogenesis, diagnosis and treatment. MOLECULAR BIOMEDICINE 2023; 4:29. [PMID: 37718386 PMCID: PMC10505605 DOI: 10.1186/s43556-023-00141-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023] Open
Abstract
Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While traditional chemotherapy and radiation therapy can improve survival outcomes for certain patients, the prognosis for extranodal lymphoma patients remains unsatisfactory. Extranodal lymphomas in different anatomical sites often have distinct cellular origins, pathogenic mechanisms, and clinical manifestations, significantly influencing their diagnosis and treatment. Therefore, it is necessary to provide a comprehensive summary of the pathogenesis, diagnosis, and treatment progress of extranodal lymphoma overall and specifically for different anatomical sites. This review summarizes the current progress in the common key signaling pathways in the development of extranodal lymphomas and intervention therapy. Furthermore, it provides insights into the pathogenesis, diagnosis, and treatment strategies of common extranodal lymphomas, including gastric mucosa-associated lymphoid tissue (MALT) lymphoma, mycosis fungoides (MF), natural killer/T-cell lymphoma (nasal type, NKTCL-NT), and primary central nervous system lymphoma (PCNSL). Additionally, as PCNSL is one of the extranodal lymphomas with the worst prognosis, this review specifically summarizes prognostic indicators and discusses the challenges and opportunities related to its clinical applications. The aim of this review is to assist clinical physicians and researchers in understanding the current status of extranodal lymphomas, enabling them to make informed clinical decisions that contribute to improving patient prognosis.
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Affiliation(s)
- Hua Yang
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, China
| | - Yang Xun
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, China
| | - Chao Ke
- Department of Neurosurgery and Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Kensuke Tateishi
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, 2360004, Japan
| | - Hua You
- Laboratory for Excellence in Systems Biomedicine of Pediatric Oncology, Department of Pediatric Hematology and Oncology, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 401122, China.
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Kumar N, Vyas A, Agnihotri SK, Chattopadhyay N, Sachdev M. Small secretory proteins of immune cells can modulate gynecological cancers. Semin Cancer Biol 2022; 86:513-531. [PMID: 35150864 DOI: 10.1016/j.semcancer.2022.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 01/27/2023]
Abstract
Small secretory proteins of immune cells are mostly Cytokines, which include chemokines, interleukins, interferons, lymphokines and tumor necrosis factors but not hormones or growth factors. These secretory proteins are the molecular messengers and primarily involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Hence, these proteins actually regulate the cells of immune system to communicate with one another to produce a synchronized, robust, still self-regulated response to a specific antigen. Chemokines are smaller secreted proteins that control overall immune cell movement and location; these chemokines are divided into 4 subgroups, namely, CXC, CC, CX3C and C according to the position of 4 conserved cysteine residues. Complete characterization of cytokines and chemokines can exploit their vast signaling networks to develop cancer treatments. These secretory proteins like IL-6, IL-10, IL-12, TNFα, CCL2, CXCL4 & CXCL8 are predominantly expressed in most of the gynecological cancers, which directly stimulate immune effector cells and stromal cells at the tumor site and augment tumor cell recognition by cytotoxic T-cells. Hence; these secretory proteins are the major regulators, which can actually modulate all kinds of gynecological cancers. Furthermore, advancements in adoptive T-cell treatment have relied on the use of multiple cytokines/chemokines to establish a highly regulated environment for anti-tumor T cell growth. A number of in vitro studies as well as animal models and clinical subjects have also shown that cytokines/chemokines have broad antitumor activity, which has been translated into a number of cancer therapy approaches. This review will focus on the foremost cytokines & chemokines involved in the majority of the gynecological malignancies and discuss their basic biology as well as clinical applications.
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Affiliation(s)
- Niranjan Kumar
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India
| | - Akanksha Vyas
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India
| | | | - Naibedya Chattopadhyay
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India.
| | - Monika Sachdev
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India.
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Markhali BP, Sriram M, Bennett DT, Khiabani PS, Hoque S, Tilley RD, Bakthavathsalam P, Gooding JJ. Single particle detection of protein molecules using dark-field microscopy to avoid signals from nonspecific adsorption. Biosens Bioelectron 2020; 169:112612. [PMID: 32977089 DOI: 10.1016/j.bios.2020.112612] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/11/2020] [Accepted: 09/12/2020] [Indexed: 10/23/2022]
Abstract
A massively parallel single particle sensing method based on core-satellite formation of Au nanoparticles was introduced for the detection of interleukin 6 (IL-6). This method exploits the fact that the localized plasmon resonance (LSPR) of the plasmonic nanoparticles will change as a result of core-satellite formation, resulting in a change in the observed color. In this method, the hue (color) value of thousands of 67 nm Au nanoparticles immobilized on a glass coverslip surface is analyzed by a Matlab code before and after the addition of reporter nanoparticles containing IL-6 as target protein. The average hue shift as the result of core-satellite formation is used as the basis to detect small amount of proteins. This method enjoys two major advantages. First it is able to analyze the hue values of thousands of nanoparticles in parallel in less than a minute. Secondly the method is able to circumvent the effect of non-specific adsorption, a major issue in the field of biosensing.
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Affiliation(s)
- Bijan P Markhali
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia
| | - Manish Sriram
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia
| | - Danielle T Bennett
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia
| | - Parisa S Khiabani
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia
| | - Sharmin Hoque
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia
| | - Richard D Tilley
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia
| | - Padmavathy Bakthavathsalam
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia.
| | - J Justin Gooding
- School of Chemistry, Australian Centre for NanoMedicine and the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of New South Wales, Sydney, 2052, Australia.
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Plasma-treated medium tunes the inflammatory profile in murine bone marrow-derived macrophages. CLINICAL PLASMA MEDICINE 2018. [DOI: 10.1016/j.cpme.2018.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Eiden L, Yamanishi C, Takayama S, Dishinger JF. Aqueous Two-Phase System Rehydration of Antibody-Polymer Microarrays Enables Convenient Compartmentalized Multiplex Immunoassays. Anal Chem 2016; 88:11328-11334. [PMID: 27808499 DOI: 10.1021/acs.analchem.6b02960] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Multiplex immunoassays are rapidly increasing in popularity due to the offered advantages of increased throughput and decreased sample volume requirements. However, a major weakness inherent to multiplex enzyme-linked immunosorbent assays (ELISA) is generation of false signals through reagent-driven cross-talk. Typically, multiplex platforms necessitate bath application of antibody cocktails, increasing probability of nonspecific antibody binding, especially when multiplexing large numbers of analytes. Aqueous two-phase systems (ATPS) exploiting the phase-separating polymers poly(ethylene) glycol (PEG) and dextran (DEX) have been used to compartmentalize antibodies and prevent cross-talk in multliplex, plate-based ELISA. However, the resulting protocol is tedious and lengthy, and requires too many user steps to be practical for widespread use. Here, we report an improved, user-friendly, cross-talk-free multiplex ELISA method in which dehydrated arrays of colocalized capture and detection antibodies in DEX are prepared on multiwell plates. Addition of a PEG-based sample buffer rehydrates antibody/DEX droplets for analysis. In this report, we demonstrate rehydrated ATPS components for multiplex ELISA retain the ability to compartmentalize antibodies and prevent cross-talk, while analytes in sample buffer partition into rehydrated DEX droplets for analysis. Utility of this method was demonstrated through successful quantitative analysis of five inflammatory cytokines in lipopolysaccharide-stimulated ThP-1 cell culture supernatant.
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Affiliation(s)
- Lisa Eiden
- PHASIQ, Inc. , Ann Arbor, Michigan 48109, United States
| | - Cameron Yamanishi
- Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Shuichi Takayama
- Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
- Department of Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States
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Bleotu C, Chifiriuc MC, Grigore R, Grancea C, Popescu CR, Anton G, Cernescu C. Investigation of Th1/Th2 cytokine profiles in patients with laryngo-pharyngeal, HPV-positive cancers. Eur Arch Otorhinolaryngol 2012; 270:711-8. [DOI: 10.1007/s00405-012-2067-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 05/03/2012] [Indexed: 10/27/2022]
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Clostridial spores for cancer therapy: targeting solid tumour microenvironment. J Toxicol 2012; 2012:862764. [PMID: 22737166 PMCID: PMC3376772 DOI: 10.1155/2012/862764] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 01/27/2012] [Indexed: 11/17/2022] Open
Abstract
Solid tumour accounts for 90% of all cancers. The current treatment approach for most solid tumours is surgery, however it is limited to early stage tumours. Other treatment options such as chemotherapy and radiotherapy are non-selective, thus causing damage to both healthy and cancerous tissue. Past research has focused on understanding tumour cells themselves, and conventional wisdom has aimed at targeting these cells directly. Recent research has shifted towards understanding the tumour microenvironment and it's differences from that of healthy cells/tissues in the body and then to exploit these differences for treatmeat of the tumour. One such approach is utilizing anaerobic bacteria. Several strains of bacteria have been shown to selectively colonize in solid tumours, making them valuable tools for selective tumour targeting and destruction. Amongst them, the anaerobic Clostridium has shown great potential in penetration and colonization of the hypoxic and necrotic areas of the tumour microenvironment, causing significant oncolysis as well as enabling the delivery of therapeutics directly to the tumour in situ. Various strategies utilizing Clostridium are currently being investigated, and represent a novel area of emerging cancer therapy. This review provides an update review of tumour microenvironment as well as summary of the progresses and current status of Clostridial spore-based cancer therapies.
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Kobawala TP, Patel GH, Gajjar DR, Patel KN, Thakor PB, Parekh UB, Patel KM, Shukla SN, Shah PM. Clinical utility of serum interleukin-8 and interferon-alpha in thyroid diseases. J Thyroid Res 2011; 2011:270149. [PMID: 21461397 PMCID: PMC3065012 DOI: 10.4061/2011/270149] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Revised: 12/02/2010] [Accepted: 12/16/2010] [Indexed: 11/20/2022] Open
Abstract
Serum interleukin-8 (IL-8) and interferon-alpha (IFN-α) levels have been estimated from a total of 88 individuals of which 19 were disease-free healthy individuals, and 69 were patients with thyroid diseases: goitre (N = 21), autoimmune diseases (N = 16), and carcinomas (N = 32). Both IL-8 and IFN-α were significantly higher in all the patients as compared to healthy individuals. Serum IL-8 levels showed significant positive correlation with disease stage in thyroid cancer patients. Higher serum IL-8 levels were associated with advanced disease stage while no significant correlation was observed between serum IFN-α levels and any of the clinicopathological parameters. IL-8 and IFN-α significantly correlated with each other in anaplastic carcinoma patients. Finally concluding, monitoring the serum IL-8 and IFN-α levels can help differentiate patients with thyroid diseases from healthy individuals, and IL-8 seems to have a role in the pathogenesis of thyroid diseases and may represent a target for innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Toral P Kobawala
- Division of Molecular Endocrinology, The Gujarat Cancer and Research Institute, NCH Compound, Asarwa, Ahmedabad 380 016, India
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Mohran ZY, Ali-Eldin FA, Abdel Aal HA. Serum interleukin-18: does it have a role in the diagnosis of hepatitis C virus related hepatocellular carcinoma? Arab J Gastroenterol 2011; 12:29-33. [PMID: 21429452 DOI: 10.1016/j.ajg.2010.11.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Revised: 09/02/2010] [Accepted: 11/18/2010] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND STUDY AIMS Early diagnosis of hepatocellular carcinoma (HCC) is the only hope for cure. Although the role of alpha foetoprotein (AFP) in the diagnosis of advanced HCC is well recognised, at least one-third of cases will be missed unless another diagnostic tool is used. Increased levels of circulating interleukin-18 (IL-18) have been observed in patients with several cancer types and were described in patients with chronic hepatitis. The aim of this study is to assess the role of serum IL-18 level in the diagnosis of hepatitis C virus (HCV)-related HCC. PATIENTS AND METHODS A total of 75 subjects categorised into four groups, including 25 patients with HCV-related HCC and AFP above 200ng/ml, 25 patients with HCV-related HCC and AFP below 200ng/ml, 15 patients with HCV-related chronic liver disease and 10 healthy controls, were enrolled. HCC was diagnosed according to guidelines of the American Association for the Study of Liver Diseases. AFP and IL-18 were assessed in all subjects. RESULTS AFP and IL-18 levels are significantly higher in patients with HCC than in disease control and healthy control subjects. IL-18 level is not correlating with the size or the number of hepatic focal lesions neither with the presence of lymphovascular invasion or abdominal lymphadenopathy. The best cut-off value of IL-18 for the diagnosis of HCC is 500pg/ml with 84% sensitivity and 86.7% specificity and the area under receiver operating characteristic curve is 0.675. CONCLUSION Serum IL-18 level is a suitable marker for the diagnosis of HCV-related HCC complementary to AFP, especially in cases with AFP level less than the diagnostic value.
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Affiliation(s)
- Zakaria Y Mohran
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, Egypt
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Badoual C, Sandoval F, Pere H, Hans S, Gey A, Merillon N, Van Ryswick C, Quintin-Colonna F, Bruneval P, Brasnu D, Fridman WH, Tartour E. Better understanding tumor-host interaction in head and neck cancer to improve the design and development of immunotherapeutic strategies. Head Neck 2010; 32:946-58. [PMID: 20191626 DOI: 10.1002/hed.21346] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Head and neck cancers are heavily infiltrated by immune cells, the significance of which is complex. The natural immune response against head and neck tumors, including anti-human papillomavirus (HPV) T cells, and humoral responses has been clearly documented. However, during the course of tumor progression, co-option of the immune system by tumor cells for their own advantage and increased resistance of tumor cells to immune attack also occur. Inflammation and immune subversion to support angiogenesis are key factors promoting tumor growth. Only a better understanding of this tumor-host interaction will permit a rational design of new immunotherapeutic approaches combining immunostimulation with drugs endowed with the ability to counteract immunoevasion mechanisms.
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Affiliation(s)
- Cécile Badoual
- EA 4054 Universite Paris Descartes, Ecole Nationale Vétérinaire d'Alfort, 7 Avenue du Général de Gaulle, 94704 Maisons Alfort, France
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Eremin O, Walker MB, Simpson E, Heys SD, Ah-See AK, Hutcheon AW, Ogston KN, Sarkar TK, Segar A, Walker LG. Immuno-modulatory effects of relaxation training and guided imagery in women with locally advanced breast cancer undergoing multimodality therapy: a randomised controlled trial. Breast 2008; 18:17-25. [PMID: 19008099 DOI: 10.1016/j.breast.2008.09.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Revised: 09/10/2008] [Accepted: 09/11/2008] [Indexed: 10/21/2022] Open
Abstract
Eighty women undergoing multimodality treatment for large (>4cm) or locally advanced (T3, T4, Tx, N2), breast cancers participated in a randomised controlled trial (RCT) to evaluate the immuno-modulatory effects of relaxation training and guided imagery. Patients underwent chemotherapy followed by surgery, radiotherapy, and hormone therapy. Those in the intervention group were taught relaxation and guided imagery. Patients kept diaries of the frequency of relaxation practice and imagery vividness. On 10 occasions during the 37 weeks following the diagnosis, blood was taken for immunological assays CD phenotyping: T cell subsets (helper, cytotoxic), natural killer (NK) and lymphokine activated killer (LAK) cells, B lymphocytes and monocytes; cytotoxicity: NK and LAK cell activities; cytokines interleukin 1 beta (1beta), 2, 4 and 6 and tumour necrosis factor alpha. Significant between-group differences were found in the number of CD25+ (activated T cells) and CD56+ (LAK cell) subsets. The number of CD3+ (mature) T cells was significantly higher following chemotherapy and radiotherapy, in patients randomised to relaxation and guided imagery. Using a median split, women who rated their imagery ratings highly had elevated levels of NK cell activity at the end of chemotherapy and at follow-up. Significant correlations were obtained between imagery ratings and baseline corrected values for NK and LAK cell activity, and IL1beta. Relaxation frequency correlated with the number of CD4+ (T helper) cells, the CD4+:8+ (helper:cytotoxic) ratio, and IL1beta levels. Relaxation training and guided imagery beneficially altered putative anti-cancer host defences during and after multimodality therapy. Such changes, to the best of our knowledge, have not been previously documented in a RCT.
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Affiliation(s)
- Oleg Eremin
- United Lincolnshire Hospitals NHS Trust, United Kingdom
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Tangkijvanich P, Thong-Ngam D, Mahachai V, Theamboonlers A, Poovorawan Y. Role of serum interleukin-18 as a prognostic factor in patients with hepatocellular carcinoma. World J Gastroenterol 2007; 13:4345-9. [PMID: 17708609 PMCID: PMC4250862 DOI: 10.3748/wjg.v13.i32.4345] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [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 whether serum interleukin-18 (IL-18) levels correlated with clinicopathologic features and prognosis in patients with hepatocellular carcinoma (HCC).
METHODS: Serum IL-18, IL-6 and IL-12 levels were measured by enzyme-linked immunosorbent assay (ELISA) from 70 patients with HCC and 10 healthy controls.
RESULTS: Serum IL-18, IL-6 and IL-12 levels of patients with HCC were significantly higher that those of the controls. The levels of IL-18 correlated significantly with the presence of venous invasion and advanced tumor stages classified by Okuda’s criteria. Patients with high serum IL-18 levels (≥ 105 pg/mL) had a poorer survival than those with low serum IL-18 levels (< 105 pg/mL) (4 and 11 mo, respectively, P = 0.015). Multivariate analyses showed that serum IL-18 level, but not IL-6 and IL-12 levels, was a significant and independent prognostic factor of survival.
CONCLUSION: These findings demonstrate that serum IL-8 may a useful biological marker of tumor invasiveness and an independent prognostic factor of survival for patients with HCC. Thus, the detailed mechanisms of IL-18 involving in tumor progression should be further investigated.
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Affiliation(s)
- Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Dai S, Zhou X, Wang B, Wang Q, Fu Y, Chen T, Wan T, Yu Y, Cao X. Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells. J Mol Med (Berl) 2006; 84:1067-76. [PMID: 17016692 PMCID: PMC7079873 DOI: 10.1007/s00109-006-0102-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2006] [Accepted: 07/05/2006] [Indexed: 01/20/2023]
Abstract
Dendritic cells (DC)-derived or tumor-derived exosomes are a population of nanometer sized membrane vesicles that can induce specific anti-tumor immunity. However, the immunogenic potential and efficiency of exosomes-based tumor vaccine are not satisfactory enough to achieve a curative effect in clinical trials. In this article we investigated whether IL-18 genetic modification of tumor cells can increase the efficacy of exosomes derived from IL-18 gene-modified tumor cells. We transfected carcinoembryonic antigen (CEA)-expressing tumor cells with a recombinant adenovirus encoding human IL-18 (AdhIL-18) and prepared the exosomes, Exo/IL-18, from IL-18 gene-modified tumor cells. We found that Exo/IL-18 naturally contain CEA and bioactive IL-18. Moreover, Exo-IL-18 are potent in chemoattracting DC and T cells, enhancing the proliferation and Th1 cytokine release of PBMC, and promoting the phenotypic and functional maturation of DC. Furthermore, Exo/IL-18-pulsed DC are quite potent to induce HLA-A*0201-restricted, CEA-specific CD8(+) CTL from the PBMC of HLA-A*0201 CEA(+) cancer patients in vitro. In almost all of these experiments, Exo/IL-18 show more potent functions than the conventionally prepared exosomes derived from parent tumor cells without IL-18 gene modification. Our findings suggest that Exo/IL-18 has more potent capability to induce specific anti-tumor immunity, and our strategy of IL-18 modification of exosomes is a feasible approach to develop exosomes-based tumor vaccines.
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Affiliation(s)
- Shengming Dai
- Institute of Immunology, Zhejiang University, Hangzhou, 310031 People’s Republic of China
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
| | - Xiangyang Zhou
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
| | - Baomei Wang
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
| | - Qingqing Wang
- Institute of Immunology, Zhejiang University, Hangzhou, 310031 People’s Republic of China
| | - Yangxin Fu
- Institute of Immunology, Zhejiang University, Hangzhou, 310031 People’s Republic of China
| | - Taoyong Chen
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
| | - Tao Wan
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
| | - Yizhi Yu
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
| | - Xuetao Cao
- Institute of Immunology, Zhejiang University, Hangzhou, 310031 People’s Republic of China
- Institute of Immunology and State Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433 People’s Republic of China
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Badoual C, Vingert B, Agueznay N, Adotevi O, Haicheur N, Molina T, Bruneval P, Fridman WH, Tartour E. [Phenotypic and functional analysis of T lymphocytes in cancer patients]. Ann Pathol 2005; 25:211-9. [PMID: 16230947 DOI: 10.1016/s0242-6498(05)80112-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
In preclinical tumor model and in human cancer, tumor antigen specific T lymphocytes play a key role in the control of tumor development. Nevertheless in numerous cases, the infiltrating tumor T cells do not seem to influence the clinical progression of the tumor. A better phenotypic and functional characterization of T cells in close contact with tumor associated with a comprehensive analysis of tumor evasion mechanism to the host response should lead to an optimization of cancer immunotherapy protocols.
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Affiliation(s)
- Cécile Badoual
- INSERM U 255, Institut Biomédical des Cordeliers, Université Paris 5
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17
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Yang C, Wu J, Zhang R, Zhang P, Eckard J, Yusuf R, Huang X, Rossman TG, Frenkel K. Caffeic acid phenethyl ester (CAPE) prevents transformation of human cells by arsenite (As) and suppresses growth of As-transformed cells. Toxicology 2005; 213:81-96. [PMID: 16085347 DOI: 10.1016/j.tox.2005.05.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2005] [Revised: 04/14/2005] [Accepted: 05/18/2005] [Indexed: 10/25/2022]
Abstract
Recent evidence suggests that inflammatory cytokines and growth factors contribute to arsenite (As)-induced human carcinogenesis. We investigated the expression of inflammatory cytokine mRNAs during the transformation process induced by chronic As exposure in non-tumorigenic human osteogenic sarcoma (N-HOS) cells using gene arrays, and results were confirmed by RT-PCR and protein arrays. Caffeic acid phenethyl ester (CAPE), a naturally occurring immunomodulating agent, was used to evaluate the role of inflammatory factors in the process of As-mediated N-HOS cell transformation and in As-transformed HOS (AsT-HOS) cells. We found that an 8-week continuous exposure of N-HOS to 0.3 microM arsenite resulted in HOS cell transformation. That exposure also caused substantial decreases in inflammatory cytokine mRNAs, such as interleukin (IL) IL-1alpha, IL-2, IL-8, IL-18, MCP-1, TGF-beta2, and TNF-alpha, while it increased c-jun mRNA in a time-dependent manner. Co-incubation of N-HOS with As and CAPE (0.5-2.5 microM) prevented As-mediated declines in cytokine mRNAs in the co-treated cells, as well as their transformation to anchorage independence, while it caused decreases in c-jun mRNA. CAPE (up to 10 microM) had no effect on growth of N-HOS cells. However, CAPE (1-10 microM) treatment of AsT-HOS cells inhibited cell growth, induced cell cycle G2/M arrest, and triggered apoptosis, accompanied by changes in cytokine gene expression, as well as decreases in cyclin B1 and cdc2 abundance. Resveratrol (RV) and (-)(.) epigallocatechin gallate (EGCG), preventive agents present in grapes and green tea, respectively, induced similar changes in AsT-HOS cell growth but required much higher doses than CAPE to cause 50% growth arrest (<2.5 microM CAPE versus 25 microM RV or 50 microM EGCG). Overall, our findings suggest that inflammatory cytokines play an important role in the suppressive effects of CAPE on As-induced cell transformation and in the selective cytotoxicity of CAPE to As-transformed HOS cells.
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Affiliation(s)
- Chengfeng Yang
- Department of Environmental Medicine and NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
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18
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Phénotypes et fonctions des lymphocytes T en pathologie tumorale. Ann Pathol 2004. [DOI: 10.1016/s0242-6498(04)94037-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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19
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Courtemanche C, Elson-Schwab I, Mashiyama ST, Kerry N, Ames BN. Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro. THE JOURNAL OF IMMUNOLOGY 2004; 173:3186-92. [PMID: 15322179 DOI: 10.4049/jimmunol.173.5.3186] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Folate is required for one-carbon transfer reactions and the formation of purines and pyrimidines for DNA and RNA synthesis. Deficiency of folate can lead to many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth defects, and carcinogenesis. The nucleotide imbalance due to folate deficiency causes cell cycle arrest in the S phase and uracil misincorporation into DNA, which may result in DNA double-strand breaks during repair. The role of folate in the immune system has not been fully characterized. We cultured PHA-activated human T lymphocytes in varying concentrations of folate, and measured proliferation, cell cycle, apoptosis, uracil misincorporation, and proportions of Th cells (CD4(+)) and cytotoxic T (CD8(+)) cells. Folate deficiency reduced proliferation of T lymphocytes, induced cell cycle arrest in the S phase, induced apoptosis, and increased the level of uracil in DNA. Folate deficiency also increased the CD4(+) to CD8(+) ratio due to a marked reduction of CD8(+) cell proliferation. Folate or nucleoside repletion of folate-deficient cells rapidly restored T lymphocyte proliferation and normal cell cycle, reduced the DNA uracil content, and lowered the CD4(+) to CD8(+) ratio. These data suggest that folate status may affect the immune system by reducing the capacity of CD8(+) cells to proliferate in response to activation.
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Affiliation(s)
- Chantal Courtemanche
- University of California, Berkeley, and Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
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20
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Abstract
Paraneoplastic peripheral neuropathies constitute a heterogeneous group of conditions. A link between the tumor and the neuropathy has been demonstrated in a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies associated with antibodies reacting with antigens common to the peripheral nervous system and the cancer. Neuropathies associated with anti-Hu antibodies are the most frequent and consist mainly in subacute sensory neuronopathy. Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent. The link between the cancer and the neuropathy is less clear in the other forms. The frequency of cancer in this group varies from 1 to 18 p.cent.These neuropathies include inflammatory demyelinating neuropathies, neuropathy and vasculitis, lower motor neurone diseases, and autonomic neuropathies. Occasionally, the neuropathy improves with treatment of the tumor. Recent data suggest that gangliosides may be the target of the immune process in neuropathies associated with melanoma.
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Affiliation(s)
- J-C Antoine
- Service de Neurologie, Hôpital Bellevue, Saint-Etienne.
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21
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Abstract
Significant progress has been made in clinicians' understanding of the molecular pathogenesis of BE, and the laboratory findings are beginning to lead to hypothesis-driven clinical studies; however, the following questions remain unanswered: (1) how can clinicians identify the persons most at risk for the development of esophageal adenocarcinoma, (2) what are the environmental gene interactions in esophageal carcinogenesis, and (3) can clinicians prevent the development of esophageal adenocarcinoma in the population at risk? As esophageal adenocarcinoma starts to reach epidemic proportions, further research in these areas is urgently required. With the advent of the genomic era and an explosion in studies in BE, significant progress can be made.
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22
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Gey A, Kumari P, Sambandam A, Lecuru F, Cassard L, Badoual C, Fridman C, Nagarajan B, Fridman WH, Tartour E. Identification and characterisation of a group of cervical carcinoma patients with profound downregulation of intratumoral Type 1 (IFNgamma) and Type 2 (IL-4) cytokine mRNA expression. Eur J Cancer 2003; 39:595-603. [PMID: 12628838 DOI: 10.1016/s0959-8049(02)00839-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Type 1 cytokines, such as interferon gamma (IFNgamma) and interleukin-2 (IL-2), increase T cell-mediated immune responses and are considered to be beneficial for antitumour immunity. Type 2 cytokines, such as IL-4, IL-5, and IL-10, inhibit Type 1 responses and promote humoral responses. We have previously reported an association between low intratumoral IFNgamma mRNA levels and poor clinical outcome in patients with invasive cervical carcinoma. In this study, by using quantitative polymerase chain reaction (PCR), we identified a group of cervical carcinoma patients with undetectable intratumoral T cell-derived cytokine mRNAs, as IFNgamma, IL-4 and IL-17 expression could not be detected in 5, 25 and 8 of the 52 biopsies analysed, respectively. Global downregulation of Type 1 and Type 2 cytokines was observed in a subgroup of patients who more frequently presented advanced stage tumours. Biopsies of patients with no IFNgamma gene expression did not appear to be less infiltrated by T cells than control biopsies with measurable IFNgamma gene expression. These results clearly demonstrate that, in some clinical situations, the decrease in intratumoral Type 1 cytokines is not associated with a Type 2 polarisation, but rather reflects global deactivation of T cells at the tumour site. These data provide support for immunotherapy protocols designed to reverse the anergic state of T cells in cancer.
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Affiliation(s)
- A Gey
- Unité d'immunologie biologique, Hopital Européen Georges Pompidou, INSERM U255, Université Pierre et Marie Curie, 20 Rue Leblanc 75908, Paris Cedex 15, France
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23
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Rutkowski P, Kaminska J, Kowalska M, Ruka W, Steffen J. Cytokine serum levels in soft tissue sarcoma patients: correlations with clinico-pathological features and prognosis. Int J Cancer 2002; 100:463-71. [PMID: 12115531 DOI: 10.1002/ijc.10496] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We investigated the correlations between serum levels of selected proinflammatory, hematopoietic and angiogenic cytokines and soluble cytokine receptors with the clinico-pathological features and prognosis in soft tissue sarcoma patients. Serum levels of 9 cytokines (TNFalpha, IL-1ra, IL-6, IL-8, IL-10, M-CSF, G-CSF, VEGF, bFGF) and 4 free cytokine receptors (sIL-2R alpha, sIL-6R, TNFRI, TNFRII) were measured by means of an enzyme-linked immunoadsorbent assay kit in 156 soft tissue sarcoma patients before the treatment and in 50 healthy controls. Serum levels of 10 cytokines and cytokine receptors were also assayed during patients' follow-up after the treatment. Significantly elevated pretreatment serum levels of 11/13 cytokines and cytokine receptors were found in sarcoma patients, as compared to healthy controls. In 40.4% of patients 6 or more cytokines and cytokine receptors (most frequently: TNF RI, IL-6, IL-8) were elevated in parallel. Serum levels of IL-6, sIL-2R, VEGF, M-CSF and TNF RI correlated significantly with tumor size and serum levels of IL-8 and IL-6 were significantly higher in patients with Grade 2/3 vs. Grade 1 tumors. We did not observe any significant differences in cytokine serum levels between patients with primary and recurrent tumors and patients with and without distant metastases. Using univariate analysis, overall survival (OS) in all patients was affected by tumor size (<5 cm vs. 5-10 cm vs. >10 cm), tumor grade (G1 vs. G2/3), presence of metastases, pretreatment serum levels of 8 cytokines (IL-6, IL-8, IL-10, sIL-2R, TNF RI, TNF RII, M-CSF, VEGF) and the number of cytokines increased (0-1 vs. 2-5 vs. < or = 6). Elevated serum levels of IL-6, IL-8, IL-10 and sIL-2R alpha, high tumor grade and larger tumor size strongly correlated with shorter disease-free survival (DFS). Multivariate analysis identified G2/3 tumor grade (p = 0.001), the presence of metastases (p = 0.004), elevated IL-6 serum level (p = 0.02), elevated IL-8 serum level (p = 0.048) and the number of cytokine serum levels above upper cut-off values (p = 0.01) as the independent prognostic factors related to OS, and G2/3 tumor grade (p = 0.005) and increased IL-6 serum level (p = 0.035) as independent prognostic factors related to DFS. In a group of patients without metastases (M0) higher tumor grade, elevated serum level of IL-6 and TNF RII, and the number of elevated cytokine serum levels correlated independently with poor survival. We found a significant decrease of several cytokine serum levels in patients after treatment (IL-1ra, IL-6, IL-8, IL-10, TNF RII, M-CSF) [p < 0.05]. Persistently elevated serum level of IL-6 after the treatment has also shown negative prognostic significance for OS (univariate analysis). Serum levels of some proinflammatory, hematopoietic and angiogenic cytokines and cytokine receptors are elevated, frequently in parallel, in a large percentage of soft tissue sarcoma patients. Significant correlations of serum cytokine levels with tumor size and grade suggest that some of these cytokines may be directly or indirectly involved in the progression of soft tissue sarcomas. Serum assays of IL-6, IL-8 and TNF RII before or after the treatment may be useful in establishing soft tissue sarcoma patients prognosis.
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Affiliation(s)
- Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcomas, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
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24
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Witz IP. Presence and functions of immune components in the tumor microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2002; 495:317-24. [PMID: 11774586 DOI: 10.1007/978-1-4615-0685-0_44] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Affiliation(s)
- I P Witz
- Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv 69978, Israel
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25
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Schweyer S, Soruri A, Baumhoer D, Peters J, Cattaruzza M, Radzun HJ, Fayyazi A. Expression of CXC chemokine IP-10 in testicular germ cell tumours. J Pathol 2002; 197:89-97. [PMID: 12081209 DOI: 10.1002/path.1094] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Tumour-infiltrating T lymphocytes (TILs) possess discrepant properties ranging from anti- to protumour activities. Understanding precisely which mechanisms navigating T lymphocytes into the tumour site will help to further the anti-tumour or to disrupt the pro-tumour activities of TILs. The present study asked what enables TILs to migrate into testicular germ cell tumours (TGCTs). TILs were characterized and the expression of a large panel of T-lymphocyte-attracting chemokines was investigated in 21 TGCT cases. Flow cytometry revealed that approximately 80% of TGCT-infiltrating T lymphocytes express CXCR3, a receptor for the chemokine interferon-inducible protein-10 (IP-10). RT-PCR and immunohistochemistry indicated that IP-10 was the only chemokine investigated which was constantly expressed in TGCT. As IP-10 was found to be expressed by endothelial cells of TGCT-associated blood vessels, the question arose whether the IP-10-regulating cytokine interferon-gamma (IFNgamma) is produced by tumour cells and if so, whether tumour-derived IFNgamma can induce IP-10 in endothelial cells. Applying in situ hybridization, IFNgamma transcripts were found in neoplastic germ cells. Analyses of two TGCT cell lines indicated that the tumour cells not only express IFNgamma mRNA, but also produce and secrete IFNgamma protein; tumour-derived IFNgamma provokes IP-10 expression and secretion by endothelial cells in vitro, as assessed by PCR and ELISA. Together, the data suggest that neoplastic germ cells secret IFNgamma and thereby stimulate tumour-associated endothelial cells to express IP-10, which contributes to the recruitment of CXCR3+ T lymphocytes to the site of TGCTs.
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MESH Headings
- Adult
- Chemokine CXCL10
- Chemokines, CXC/metabolism
- Chemotaxis, Leukocyte/immunology
- Endothelium, Vascular/immunology
- Gene Expression
- Humans
- In Situ Hybridization
- Interferon-gamma/biosynthesis
- Interferon-gamma/genetics
- Lymphocytes, Tumor-Infiltrating/immunology
- Male
- Middle Aged
- Neoplasms, Germ Cell and Embryonal/immunology
- RNA, Messenger/genetics
- RNA, Neoplasm/genetics
- Receptors, CXCR3
- Receptors, Chemokine/metabolism
- Testicular Neoplasms/immunology
- Tumor Cells, Cultured
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Affiliation(s)
- S Schweyer
- Department of Pathology, Georg-August-University Göttingen, Germany.
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26
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Eshel R, Neumark E, Sagi-Assif O, Witz IP. Receptors involved in microenvironment-driven molecular evolution of cancer cells. Semin Cancer Biol 2002; 12:139-47. [PMID: 12027586 DOI: 10.1006/scbi.2001.0422] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Cells, including cancer cells, communicate with their microenvironment via various types of membrane receptors. An important down-stream effect of such interactions is a change in the molecular phenotype of the cells. The microenvironment-driven molecular evolution of cancer cells may induce either growth arrest or death of the cells or alternatively, boost their malignancy phenotype. In this paper we summarize studies from our own laboratory on interactions of cancer cells with microenvironmental ligands via two types of receptors that are not commonly associated with tumour progression i.e. the receptor for the Fc portion of IgG, and Ly-6 proteins of mouse and human origin. We also review information on interactions of tumour-associated chemokines and chemokine receptors with the corresponding microenvironmental factors. We demonstrate how these interactions may drive the molecular evolution of tumour cells and discuss the possible impact of this evolution on tumour progression.
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Affiliation(s)
- Rinat Eshel
- Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
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27
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Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautès-Fridman C, Fossiez F, Haicheur N, Fridman WH, Tartour E. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 2002; 99:2114-21. [PMID: 11877287 DOI: 10.1182/blood.v99.6.2114] [Citation(s) in RCA: 254] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Interleukin 17 (IL-17) is a proinflammatory cytokine produced by activated CD4(+) memory T cells. We previously showed that IL-17 increased the growth rate of human cervical tumors transplanted into athymic nude mice. To address the possible role of T cells in the biologic activity of IL-17 for tumor control, we grafted 2 murine hematopoietic immunogenic tumors (P815 and J558L) transfected with a complementary DNA encoding murine IL-17 into syngeneic immunocompetent mice. We found that growth of the 2 IL-17-producing tumors was significantly inhibited compared with that of mock-transfected tumors. In contrast to the antitumor activity of IL-17 observed in immunocompetent mice, we observed no difference in the in vivo growth of IL-17-transfected or mock-transfected P815 cells (P815-IL-17 and P815-Neo, respectively) transplanted into nude mice. We then showed that IL-17 increased generation of specific cytolytic T lymphocytes (CTLs) directed against the immunodominant antigens from P815 called A, B, C, D, and E, since all mice injected with P815-IL-17 developed a P815-specific CTL response, whereas only 6 of 16 mice immunized with P815-Neo had a specific CTL response against the antigens. The induction of CTLs was associated with establishment of a tumor-protective immunity. These experiments suggest that T lymphocytes are involved in the antitumor activity of IL-17. Therefore, IL-17, like other cytokines, appears to be a pleiotropic cytokine with possible protumor or antitumor effects on tumor development, which often depends on the immunogenicity of tumor models.
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Affiliation(s)
- Fabrice Benchetrit
- INSERM U 255, Université Pierre et Marie Curie, Hopital Européen Georges Pompidou, 20 Rue Leblanc, 75908 Paris Cedex 15, France
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28
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Poloso NJ, Nagarajan S, Mejia-Oneta JM, Selvaraj P. GPI-anchoring of GM-CSF results in active membrane-bound and partially shed cytokine. Mol Immunol 2002; 38:803-16. [PMID: 11922938 DOI: 10.1016/s0161-5890(02)00005-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce the generation and activation of dendritic cells (DCs), the most potent of antigen presenting cells (APCs). Tumors secreting GM-CSF have been shown to induce strong anti-tumor immune responses. In this report, we have constructed a glycosylphosphatidyl-inositol (GPI) anchored form of GM-CSF (GPI-GM-CSF). This protein subsequently was found expressed on the cell membrane and sensitive to phosphatidyl-inositol-specific phospholipase C (PIPLC), confirming that it is GPI-anchored. However, GM-CSF was also found in the culture supernatant of cells expressing GPI-GM-CSF. Inhibition studies using brefeldin A and para-formaldehyde fixation revealed that GM-CSF found in the supernatant was not secreted, but due to shedding or proteolytic cleavage. Accumulation of GM-CSF in the media from isolated membranes was time and temperature-dependent. The released portion represented 10-15% of all membrane-bound GM-CSF after 72h under culture conditions. GPI-GM-CSF retained functional activity to induce bone marrow cell proliferation and administration of GPI-GM-CSF expressing membranes induced the generation of DCs in vivo. These results demonstrate that GPI-anchored GM-CSF retains all functional activity of native GM-CSF while gaining the ability to attach to cell membranes. The ability of GPI-GM-CSF to be expressed on membranes and be partially released, can possibly lead to formation of a cytokine gradient, while retaining ability to target associated membrane antigens to DCs. This novel form of GM-CSF may have wide range of clinical applicability.
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Affiliation(s)
- Neil J Poloso
- Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, 1639 Pierce Drive, Woodruff Memorial Building, Room 7309, Atlanta, GA 30322, USA
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29
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Ruiter D, Bogenrieder T, Elder D, Herlyn M. Melanoma-stroma interactions: structural and functional aspects. Lancet Oncol 2002; 3:35-43. [PMID: 11905603 DOI: 10.1016/s1470-2045(01)00620-9] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Cutaneous melanomas are notorious for their tendency to metastasise. Because the tumour microenvironment plays an important part in tumour development and progression, we review the structural and functional aspects of interactions between melanoma and the stroma. We emphasise fibrovascular patterns (both in uveal and cutaneous melanoma), cellular and extracellular composition of the stroma, and the molecules involved. Also, we discuss functional interactions, focusing on melanoma-fibroblast cross-talk by soluble factors and by direct cell-cell contact. On the basis of recent findings we propose that involvement of fibroblasts in melanoma-stromagenesis occurs through different stages: recruitment, activation, and conversion to myofibroblasts, or differentiation to fibrocytes. We reason that this involvement is topographically linked to different areas in and around the tumour, and hypothesise that stromal activation, as seen in tumor ulceration or immunological regression in melanoma, stimulates tumour progression.
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Affiliation(s)
- Dirk Ruiter
- The Wistar Institute, Philadelphia, PA, USA.
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30
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Nagtegaal ID, Marijnen CAM, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJH, van Krieken JHJM. Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect--a histopathological and immunohistochemical study. BMC Cancer 2001; 1:7. [PMID: 11481031 PMCID: PMC35356 DOI: 10.1186/1471-2407-1-7] [Citation(s) in RCA: 110] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2001] [Accepted: 07/16/2001] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Invasion and metastasis is a complex process governed by the interaction of genetically altered tumor cells and the immunological and inflammatory host response. Specific T-cells directed against tumor cells and the nonspecific inflammatory reaction due to tissue damage, cooperate against invasive tumor cells in order to prevent recurrences. Data concerning involvement of individual cell types are readily available but little is known about the coordinate interactions between both forms of immune response. PATIENTS AND METHODS The presence of inflammatory infiltrate and eosinophils was determined in 1530 patients with rectal adenocarcinoma from a multicenter trial. We selected 160 patients to analyze this inflammatory infiltrate in more detail using immunohistochemistry. The association with the development of local and distant relapses was determined using univariate and multivariate log rank testing. RESULTS Patients with an extensive inflammatory infiltrate around the tumor had lower recurrence rates (3.4% versus 6.9%, p = 0.03), showing the importance of host response against tumor cells. In particular, peritumoral mast cells prevent local and distant recurrence (44% versus 15%, p = 0.007 and 86% versus 21%, p < 0.0001, respectively), with improved survival as a consequence. The presence of intratumoral T-cells had independent prognostic value for the occurrence of distant metastases (32% versus 76%, p < 0.0001). CONCLUSIONS We showed that next to properties of tumor cells, the amount and type of inflammation is also relevant in the control of rectal cancer. Knowledge of the factors involved may lead to new approaches in the management of rectal cancer.
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Affiliation(s)
- Iris D Nagtegaal
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
- Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Pathology, University Medical Centre St. Radboud, Nijmegen, the Netherlands
| | - Corrie AM Marijnen
- Surgery, Leiden University Medical Center, Leiden, the Netherlands
- Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Adri Mulder-Stapel
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Jo Hermans
- Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands
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31
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Shoham T, Sternberg D, Brosh N, Krupsky M, Barda-Saad M, Zipori D. The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A. Leukemia 2001; 15:1102-10. [PMID: 11455980 DOI: 10.1038/sj.leu.2402145] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The mesenchymal stroma has been shown to play a crucial role in the development of multiple myeloma, partly by secretion of interleukin (IL)-6, that serves as a growth factor for myeloma cells. However, it is still unclear which other stromal molecules are involved in the pathogenesis of this disease. We chose, as a model system, a mouse plasmacytoma cell line, which does not respond to IL-6. We found that the formation of mouse plasmacytoma tumors, in an in vivo skin transplantation model, is facilitated by co-injection of these tumor cells along with a mesenchymal stromal cell. The tumor promoting effect of the stroma was reproduced in an in vitro model; stromal cells induced the proliferation of plasmacytoma cells under serum-free conditions. This growth promotion could not be mimicked by a series of cytokines including IL-6 and insulin-like growth factor (IGF)-I implying a role for yet unidentified stromal factors. The in vivo formation of plasmacytoma tumors was reduced following administration of activin A, a cytokine member of the transforming growth factor (TGF)beta superfamily. Furthermore, the in vitro growth promoting effect of the stroma was abrogated by basic fibroblast growth factor (bFGF) which induced a higher stromal expression of activin A. Our results thus show that mesenchymal stroma expresses plasmacytoma growth stimulating activities that overcome the low constitutive level of the plasmacytoma inhibitor, activin A. The expression of activin A is upregulated by bFGF rendering the stroma suppressive for plasmacytoma growth. The balance between the expression of these regulators may contribute to mesenchymal stroma activity and influence the progression of multiple myeloma.
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Affiliation(s)
- T Shoham
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
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32
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Pages F, Berger A, Lebel-Binay S, Zinzindohoue F, Danel C, Piqueras B, Carriere O, Thiounn N, Cugnenc PH, Fridman WH. Proinflammatory and antitumor properties of interleukin-18 in the gastrointestinal tract. Immunol Lett 2000; 75:9-14. [PMID: 11163860 DOI: 10.1016/s0165-2478(00)00285-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Interleukin-18 (IL-18) plays a central role in the immune response by acting on Th1 cell differentiation, cell-mediated cytotoxicity and inflammation. The role of IL-18 in cancers and inflammatory diseases is discussed in the light of our investigations on IL-18 synthesis in normal colonic mucosa, colonic cancer and Crohn's disease (CD).
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Affiliation(s)
- F Pages
- Laboratoire Universitaire de Transfert en Immunologie, Universités Paris V, Paris VI/Laboratorie Pierre Fabre, France.
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Fitzgerald RC, Farthing MJ. The pathogenesis of Barrett's esophagus: a process in continuum or discontinuum. Curr Gastroenterol Rep 2000; 2:421-4. [PMID: 11079041 DOI: 10.1007/s11894-000-0001-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- R C Fitzgerald
- Faculty of Medicine, University of Glasgow, Southpark Terrace, Glasgow G12 8LG, Scotland
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Tartour E, Mehtali M, Sastre-Garau X, Joyeux I, Mathiot C, Pleau JM, Squiban P, Rochlitz C, Courtney M, Jantscheff P, Herrmann R, Pouillart P, Fridman WH, Dorval T. Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings. Br J Cancer 2000; 83:1454-61. [PMID: 11076653 PMCID: PMC2363414 DOI: 10.1054/bjoc.2000.1492] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Various studies have emphasized an immunodepression state observed at the tumour site. To reverse this defect and based upon animal studies, we initiated a phase I clinical trial of gene therapy in which various doses of xenogeneic monkey fibroblasts (Vero cells) genetically engineered to produce human IL-2 were administered intratumorally in 8 patients with metastatic solid tumours. No severe adverse effect was observed in the 8 patients analysed during this clinical trial even in the highest dose (5 yen 107 cells) group. This absence of toxicity seems to be associated with rapid elimination of Vero-IL-2 cells from the organism. Indeed, exogenous IL-2 mRNA could no longer be detected in the peripheral whole blood 48 hours after Vero-IL-2 cell administration. In addition, we did not find any expression of exogenous IL-2 mRNA in post-therapeutic lesions removed 29 days after the start of therapy. A major finding of this trial concerns the two histological responses of two treated subcutaneous nodules not associated with an apparent clinical response. The relationship between local treatment and tumour regression was supported by replacement of tumour cells by inflammatory cells in regressing lesions and marked induction of T and natural killer cell derived cytokines (IL-2, IL-4, IFNg ...) in post-therapeutic lesions analysed 28 days after the start of Vero-IL-2 administration. Gene therapy using xenogeneic cells as vehicle may therefore present certain advantages over other vectors, such as its complete absence of toxicity. Furthermore, the in vivo biological effect of immunostimulatory genes, i.e IL-2-, may be potentiated by the xenogeneic rejection reaction.
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Affiliation(s)
- E Tartour
- Department of Tumor Biology, Institut Curie, Université Pierre et Marie Curie, Paris, France
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Tirunagaru VG, Sofer L, Cui J, Burnside J. An expressed sequence tag database of T-cell-enriched activated chicken splenocytes: sequence analysis of 5251 clones. Genomics 2000; 66:144-51. [PMID: 10860659 DOI: 10.1006/geno.2000.6189] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The cDNA and gene sequences of many mammalian cytokines and their receptors are known. However, corresponding information on avian cytokines is limited due to the lack of cross-species activity at the functional level or strong homology at the molecular level. To improve the efficiency of identifying cytokines and novel chicken genes, a directionally cloned cDNA library from T-cell-enriched activated chicken splenocytes was constructed, and the partial sequence of 5251 clones was obtained. Sequence clustering indicates that 2357 (42%) of the clones are present as a single copy, and 2961 are distinct clones, demonstrating the high level of complexity of this library. Comparisons of the sequence data with known DNA sequences in GenBank indicate that approximately 25% of the clones match known chicken genes, 39% have similarity to known genes in other species, and 11% had no match to any sequence in the database. Several previously uncharacterized chicken cytokines and their receptors were present in our library. This collection provides a useful database for cataloging genes expressed in T cells and a valuable resource for future investigations of gene expression in avian immunology. A chicken EST Web site (http://udgenome. ags.udel. edu/chickest/chick.htm) has been created to provide access to the data, and a set of unique sequences has been deposited with GenBank (Accession Nos. AI979741-AI982511). Our new Web site (http://www. chickest.udel.edu) will be active as of March 3, 2000, and will also provide keyword-searching capabilities for BLASTX and BLASTN hits of all our clones.
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Affiliation(s)
- V G Tirunagaru
- Department of Animal and Food Sciences, University of Delaware, Newark, Delaware, 19717-1303, USA
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Haicheur N, Escudier B, Dorval T, Negrier S, De Mulder PH, Dupuy JM, Novick D, Guillot T, Wolf S, Pouillart P, Fridman WH, Tartour E. Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients. Clin Exp Immunol 2000; 119:28-37. [PMID: 10606961 PMCID: PMC1905550 DOI: 10.1046/j.1365-2249.2000.01112.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/1999] [Indexed: 12/12/2022] Open
Abstract
This study shows that subcutaneous administration of increasing doses of IL-12, once a week, in 21 cancer patients increased the expression of cytokine genes (interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), IP-10, MIG, IL-10, IL-4) in peripheral blood mononuclear cells even at very low doses (30 ng/kg). Surprisingly, no circulating TNF-alpha or IL-4 could be detected in the plasma of patients treated with IL-12. However, a marked increase of soluble IL-4 receptor was demonstrated in the plasma of five of the six patients studied, which may represent an additional mechanism by which IL-12 inhibits the development of the Th2 response in vivo. A marked decline of IFN-gamma and IP10 induction was recorded after repeated cycles of IL-12. In contrast, in most patients IL-12 increased IL-10 expression with no subsequent decrease during the course of therapy, and even an earlier peak of IL-10 induction at the 6th cycle. In addition, a constant up-regulation of serum soluble IFN-gamma receptor levels was observed after each cycle of IL-12 treatment with a delayed peak compared with the IFN-gamma peak. The constant rise of IL-10 and soluble IFN-gamma receptor during IL-12 therapy may therefore contribute to the inhibition of IFN-gamma activity detected after repeated cycles of IL-12. Lastly, a marked heterogeneity of cytokine induction was observed from one patient to another, which appeared to be independent of the dose of IL-12 administered. These data may lead to a better understanding of the biological activity of IL-12 and the in vivo mechanisms of its regulation.
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MESH Headings
- Antineoplastic Agents/blood
- Base Sequence
- Chemokine CXCL9
- Chemokines/blood
- Chemokines/genetics
- Chemokines, CXC/blood
- Chemokines, CXC/genetics
- Cytokines/blood
- Cytokines/genetics
- DNA Primers/genetics
- Dose-Response Relationship, Drug
- Gene Expression/drug effects
- Humans
- Intercellular Signaling Peptides and Proteins
- Interferon-gamma/blood
- Interferon-gamma/genetics
- Interleukin-10/blood
- Interleukin-10/genetics
- Interleukin-12/administration & dosage
- Interleukin-12/therapeutic use
- Interleukin-4/blood
- Interleukin-4/genetics
- Neoplasms/drug therapy
- Neoplasms/genetics
- Neoplasms/immunology
- Neovascularization, Pathologic/prevention & control
- RNA, Messenger/blood
- RNA, Messenger/genetics
- Receptors, Cytokine/blood
- Receptors, Cytokine/genetics
- Receptors, Interleukin-4/blood
- Receptors, Interleukin-4/genetics
- Recombinant Proteins/administration & dosage
- Recombinant Proteins/therapeutic use
- Solubility
- Th1 Cells/immunology
- Th2 Cells/immunology
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- N Haicheur
- Unité d'Immunologie Clinique, INSERM 255, Institut Curie, Paris
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