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Song S, Liu S, Wei Z, Jin X, Mao D, He Y, Li B, Zhang C. Identification of an Immune-Related Long Noncoding RNA Pairs Model to Predict Survival and Immune Features in Gastric Cancer. Front Cell Dev Biol 2021; 9:726716. [PMID: 34621744 PMCID: PMC8491937 DOI: 10.3389/fcell.2021.726716] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/26/2021] [Indexed: 11/25/2022] Open
Abstract
Background: Gastric cancer (GC) remains one of the most malignant tumors around the world, and an accurate model that reliably predicts survival and therapeutic efficacy is urgently needed. As a novel predictor for prognosis in a variety of cancers, immune-related long noncoding RNA pairs (IRlncRNAPs) have been reported to predict tumor prognosis. Herein, we integrated an IRlncRNAPs model to predict the clinical outcome, immune features, and chemotherapeutic efficacy of GC. Methods: Based on the GC data obtained from The Cancer Genome Atlas (TCGA) database and the Immunology Database and Analysis Portal (ImmPort), differentially expressed immune-related long noncoding RNAs (DEIRlncRNAs) were identified. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis were used to select the most appropriate overall survival (OS)-related IRlncRNAPs to develop a prognostic signature. The riskScore of each sample was calculated by comparing the long noncoding RNA expression level in each IRlncRNAP. Based on the riskScore for each patient, GC patients were divided into high- and low-risk groups. Then, the correlation of the signature and riskScore with OS, clinical features, immune cell infiltration, immune-related gene (IRG) expression and chemotherapeutic efficacy in GC was analyzed. Results: A total of 107 DEIRlncRNAs were identified which formed 4297 IRlncRNAPs. Fifteen OS-related IRlncRNAPs were selected to develop a prognostic model. GC patients could be accurately classified into high- and low-risk groups according to the riskScore of the prognostic model. The 1-, 2-, 3-, and 5-year receiver operating characteristic (ROC) curves for the riskScore were drawn and the area under the curve (AUC) values were found to be 0.788, 0.810, 0.825, and 0.868, respectively, demonstrating a high sensitivity and accuracy of this prognostic signature. Moreover, the immune-related riskScore was an independent risk factor. Patients showed a poorer outcome within the high-risk group. In addition, the riskScore was found to be significantly correlated with the clinical features, immune infiltration status, IRG expression, and chemotherapeutic efficacy in GC. Conclusion: The prognostic model of IRlncRNAPs offers great promise in predicting the prognosis, immune infiltration status, and chemotherapeutic efficacy in GC, which might be helpful for the selection of chemo- and immuno-therapy of GC.
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Affiliation(s)
- Shenglei Song
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuhao Liu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhewei Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xinghan Jin
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Deli Mao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Bo Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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Lv Y, Song M, Tian X, Yv X, Liang N, Zhang J. Impact of radiotherapy on circulating lymphocyte subsets in patients with esophageal cancer. Medicine (Baltimore) 2020; 99:e20993. [PMID: 32898991 PMCID: PMC7478455 DOI: 10.1097/md.0000000000020993] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Radiotherapy (RT) can affect the immune function of patients with cancer. The purpose of this study was to investigate the effect of RT on lymphocyte and its subsets in patients with esophageal cancer (EC).All patients received RT with a mean dose of 5369 cGy (gray). Blood parameters were measured in 31 patients on 3 occasions (before, at the end of radiotherapy, and at 3 months follow-up). The whole blood count and lymphocyte subsets were measured and correlated with short time efficiency and radiation dose parameters.White blood count (WBC) and lymphocyte count (ALC) were greatly decreased at the end of radiotherapy, and the percentages of CD3+, CD3+CD8+ T cells were significantly increased, on the other hand, a decrease in the CD4/CD8 ratio was observed. The percentages of CD3-CD16/56+NK cells and CD19+ B cell were decreased at the end of RT compared with prior RT. The percentages of CD3+ T cells before RT and the WBC and ALC count after RT can be used as prognostic indicators for survival. The PTV dose can cause significant changes in lymphocytes count after RT. CD3+T cells after RT were significantly correlated with mean heart dose and heart V50.Our study identified that RT causes changes in lymphocyte subsets, and these changes may indicate differences in immune function between individuals. Radiotherapy plan should be designed to minimize normal tissue dose to reduce the impact on WBC and lymphocytes.
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Affiliation(s)
- Yajuan Lv
- Shandong Provincial Qianfoshan Hospital, Shandong University
| | - Meijuan Song
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Xiufang Tian
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Xinshuang Yv
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Ning Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Jiandong Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
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Wang T, Zhang Z, Xing H, Wang L, Zhang G, Yu N, Wang J, Guo W, Jiang J. Elevated Th22 cells and related cytokines in patients with epithelial ovarian cancer. Medicine (Baltimore) 2017; 96:e8359. [PMID: 29069020 PMCID: PMC5671853 DOI: 10.1097/md.0000000000008359] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
This study is conducted to investigate the involvement of T-helper (Th) cells and regulatory T cells in epithelial ovarian cancer (EOC).The percentages of Th22, Th17, Th1, and regulatory T cells in the peripheral blood of EOC patients, benign ovarian epithelial neoplasm (BOEN) patients, and healthy control (HC) were examined by flow cytometry. Enzyme-linked immunosorbent assay was used to determine serum levels of interleukin (IL)-22, IL-17, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α).Th22 and Th17 were significantly increased in EOC patients. The plasma concentrations of IL-22 and TNF-α were significantly elevated in EOC patients compared with BOEN patients and HC. In EOC patients, there was an increased trend of Th22, IL-22, and TNF-α in stage III-IV patients compared with stage I-II patients. A positive correlation was seen among Th22, Th17, and Th1 cells in EOC patients. Similarly, positive correlations were detected between Th22 cells and IL-22 or TNF-α and between Th1 cells and interferon-γ (IFN-γ) in EOC patients. Besides, no significant difference was found in Th1 cells and regulatory T cells among EOC and BOEN patients and HC.There is a higher circulating frequency of Th22, Th17 cells, IL-22, and TNF-α concentration in EOC patients, which may conjointly participate in the pathogenesis and growth of EOC.
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Affiliation(s)
- Ting Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Zhiwei Zhang
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Huaixin Xing
- Department of Anesthesiology, Shandong Cancer Hospital
| | - Li Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Guoxiang Zhang
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Na Yu
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Junzhi Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Wei Guo
- Department of Obstetrics and Gynecology, Shandong Provincial Qianfoshan Hospital
| | - Jie Jiang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, P.R. China
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Goyvaerts C, Kurt DG, Van Lint S, Heirman C, Van Ginderachter JA, De Baetselier P, Raes G, Thielemans K, Breckpot K. Immunogenicity of targeted lentivectors. Oncotarget 2015; 5:704-15. [PMID: 24519916 PMCID: PMC3996667 DOI: 10.18632/oncotarget.1680] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
To increase the safety and possibly efficacy of HIV-1 derived lentivectors (LVs) as an anti-cancer vaccine, we recently developed the Nanobody (Nb) display technology to target LVs to antigen presenting cells (APCs). In this study, we extend these data with exclusive targeting of LVs to conventional dendritic cells (DCs), which are believed to be the main cross-presenting APCs for the induction of a TH1-conducted antitumor immune response. The immunogenicity of these DC-subtype targeted LVs was compared to that of broad tropism, general APC-targeted and non-infectious LVs. Intranodal immunization with ovalbumin encoding LVs induced proliferation of antigen specific CD4+ T cells, irrespective of the LVs' targeting ability. However, the cytokine secretion profile of the restimulated CD4+ T cells demonstrated that general APC targeting induced a similar TH1-profile as the broad tropism LVs while transduction of conventional DCs alone induced a similar and less potent TH1 profile as the non-infectious LVs. This observation contradicts the hypothesis that conventional DCs are the most important APCs and suggests that the activation of other APCs is also meaningful. Despite these differences, all targeted LVs were able to stimulate cytotoxic T lymphocytes, be it to a lesser extent than broad tropism LVs. Furthermore this induction was shown to be dependent on type I interferon for the targeted and non-infectious LVs, but not for broad tropism LVs. Finally we demonstrated that the APC-targeted LVs were as potent in therapy as broad tropism LVs and as such deliver on their promise as safer and efficacious LV-based vaccines.
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Affiliation(s)
- Cleo Goyvaerts
- Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium
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Pan L, Weng R, Zhang J, Wang J, Tang Y, Deng N. Immune Response of the VEGF/bFGF Complex Peptide Vaccine and Function of Immune Antibodies in Inhibiting Migration of HUVEC Cells and Proliferation of Cancer Cells. Int J Pept Res Ther 2014. [DOI: 10.1007/s10989-014-9414-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Sharma RK, Yolcu ES, Srivastava AK, Shirwan H. CD4+ T cells play a critical role in the generation of primary and memory antitumor immune responses elicited by SA-4-1BBL and TAA-based vaccines in mouse tumor models. PLoS One 2013; 8:e73145. [PMID: 24066030 PMCID: PMC3774737 DOI: 10.1371/journal.pone.0073145] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 07/17/2013] [Indexed: 12/20/2022] Open
Abstract
The role of CD4+ T cells in the generation of therapeutic primary and memory immune responses in cancer diverse immunotherapy settings remains ambiguous. We herein investigated this issue using two vaccine formulations containing a novel costimulatory molecule, SA-4-1BBL, as adjuvant and HPV E7 or survivin (SVN) as tumor associated antigens (TAAs) in two mouse transplantable tumor models; the TC-1 cervical cancer expressing xenogeneic HPV E7 and 3LL lung carcinoma overexpressing autologous SVN. Single vaccination with optimized SA-4-1BBL/TAA formulations resulted in the eradication of 6-day established TC-1 and 3LL tumors in >70% of mice in both models. The in vivo depletion of CD4+ T cells one day before tumor challenge resulted in compromised vaccine efficacy in both TC-1 (25%) and 3LL (12.5%) tumor models. In marked contrast, depletion of CD4+ T cells 5 days post-tumor challenge and one day prior to vaccination did not significantly alter the therapeutic efficacy of these vaccines. However, long-term immunological memory was compromised in the 3LL, but not in TC-1 model as a significant number (85.7%) of tumor free-mice succumbed to tumor growth when rechallenged with 3LL cells 60 days after the initial tumor inoculation. Collectively, these results demonstrate the indispensable role CD4+ T cells play in the generation of therapeutic primary immune responses elicited by SA-4-1BBL/TAA-based vaccines irrespective of the nature of TAAs and establish the importance of CD4+ T cells for long-term immune memory against 3LL tumor expressing self-antigen SVN, but not TC-1 expressing xenogeneic viral antigen E7.
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Affiliation(s)
- Rajesh K. Sharma
- Institute for Cellular Therapeutics, Department of Microbiology and Immunology and James Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America
| | - Esma S. Yolcu
- Institute for Cellular Therapeutics, Department of Microbiology and Immunology and James Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America
| | - Abhishek K. Srivastava
- Institute for Cellular Therapeutics, Department of Microbiology and Immunology and James Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America
| | - Haval Shirwan
- Institute for Cellular Therapeutics, Department of Microbiology and Immunology and James Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America
- * E-mail:
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7
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CD4+ T lymphocytes are critical mediators of tumor immunity to simian virus 40 large tumor antigen induced by vaccination with plasmid DNA. J Virol 2011; 85:7216-24. [PMID: 21593176 DOI: 10.1128/jvi.00543-11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A mechanistic analysis of tumor immunity directed toward the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory for scenarios of recombinant Tag immunization in BALB/c mice. In the present study, we performed a preliminary characterization of the immune components necessary for systemic tumor immunity induced upon immunization with plasmid DNA encoding SV40 Tag as a transgene (pCMV-Tag). Antibody responses to SV40 Tag were observed via indirect enzyme-linked immunosorbent assay following three intramuscular (i.m.) injections of pCMV-Tag and were typified by a mixed Th1/Th2 response. Complete tumor immunity within a murine model of pulmonary metastasis was achieved upon two i.m. injections of pCMV-Tag, as assessed by examination of tumor foci in mouse lungs, without a detectable antibody response to SV40 Tag. Induction-phase and effector-phase depletions of T cell subsets were performed in vivo via administration of depleting rat monoclonal antibodies, and these experiments demonstrated that CD4(+) T lymphocytes are required in both phases of the adaptive immune response. Conversely, depletion of CD8(+) T lymphocytes did not impair tumor immunity in either immune phase and resulted in the premature production of antibodies to SV40 Tag. Our findings are unique in that a dominant role could be ascribed to CD4(+) T lymphocytes within a model of DNA vaccine-induced tumor immunity to Tag-expressing tumor cells. Additionally, our findings provide insight into the general mechanisms of vaccine-induced tumor immunity directed toward tumors bearing distinct tumor-associated antigens.
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8
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Ling Y, Fan L, Dong C, Zhu J, Liu Y, Ni Y, Zhu C, Zhang C. Combined influence of adjuvant therapy and interval after surgery on peripheral CD4(+) T lymphocytes in patients with esophageal squamous cell carcinoma. Exp Ther Med 2010; 1:113-120. [PMID: 23136603 DOI: 10.3892/etm_00000020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 10/26/2009] [Indexed: 11/06/2022] Open
Abstract
The aim of this study was to investigate possible differences in cellular immunity between chemo- and/or radiotherapy groups during a long interval after surgery in esophageal squamous cell carcinoma (ESCC) patients. Cellular immunity was assessed as peripheral lymphocyte subsets in response to chemotherapy (CT), radiotherapy (RT) and CT+RT by flow cytometric analysis. There were 139 blood samples obtained at different time points relative to surgery from 73 patients with ESCC. The changes in the absolute and relative proportions of lymphocyte phenotypes were significant among the adjuvant therapy groups. There were significant differences in the absolute counts of CD4(+) and CD8(+) T cells among the interval groups, and a lower CD4/CD8 ratio was found in patients following a prolonged interval. RT alone had a profound effect on the absolute counts of CD3(+), CD4(+) and CD8(+) T cells compared with the other groups. CD4(+) T cells exhibited a decreasing trend during a long interval, leading to a prolonged T-cell imbalance after surgery. Univariate analysis revealed that the interaction of the type of adjuvant therapy and the interval after surgery was correlated only with the percentage of CD4(+) T cells. The percentage of CD4(+) T cells can be used as an indicator of the cellular immunity after surgery in ESCC patients. However, natural killer cells consistently remained suppressed in ESCC patients following adjuvant therapy after surgery. These findings confirm an interaction between adjuvant therapy and the interval after surgery on peripheral CD4(+) T cells, and implies that adjuvant therapy may have selective influence on the cellular immunity of ESCC patients after surgery.
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Affiliation(s)
- Yang Ling
- Laboratory of Clinical Oncology, Changzhou Tumor Hospital, Medical College of Soochow University, Jiangsu
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9
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Chen PW, Ksander BR. Termination of Systemic Immunity in the Presence of Intraocular Tumors: Influence of Ocular Immune Privilege on Tumor Vaccines. Curr Eye Res 2009; 31:43-55. [PMID: 16421019 DOI: 10.1080/02713680500477339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Ocular immune privilege preserves the visual axis by preventing the induction of sight-threatening nonspecific inflammation. Although privilege is essential for maintaining visual integrity, intraocular tumors exploit the privileged environment and grow progressively within the anterior chamber of the eye. Recently, a large number of laboratories have constructed genetically engineered tumor cell vaccines that express high levels of costimulatory signals. These vaccines are designed to bypass the normal pathways of T-cell activation and directly activate CD8+ tumor-specific T cells. In the following series of experiments, we determined whether a tumor cell vaccine that uses costimulatory signals (CD80 and IL-12) is capable of eliminating tumors within the immune-privileged anterior chamber. As expected, vaccine-immunized mice rejected subcutaneous flank tumors (a non-privileged site). However, the vaccine failed to protect mice from even a small number of tumor cells transplanted into the immune-privileged anterior chamber. Surprisingly, immunized mice that were simultaneously challenged with subcutaneous and anterior chamber tumors were unable to eliminate tumors at either site. The failure of systemic protective immunity coincided with the loss of tumor-specific delayed hypersensitivity and cytotoxic T cells. We conclude that tumor cell vaccines that induce complete protection against tumors in non-immune-privileged sites fail to protect against the same tumor within an ocular immune-privileged site. Moreover, a tumor that escapes elimination within the eye can terminate systemic protective immunity that is induced by the tumor cell vaccine.
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Affiliation(s)
- Peter W Chen
- Department of Ophthalmology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9057, USA.
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10
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Jacobs JFM, Coulie PG, Figdor CG, Adema GJ, de Vries IJM, Hoogerbrugge PM. Targets for active immunotherapy against pediatric solid tumors. Cancer Immunol Immunother 2009; 58:831-41. [PMID: 19009292 PMCID: PMC11030767 DOI: 10.1007/s00262-008-0619-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2008] [Accepted: 10/22/2008] [Indexed: 02/06/2023]
Abstract
The potential role of antibodies and T lymphocytes in the eradication of cancer has been demonstrated in numerous animal models and clinical trials. In the last decennia new strategies have been developed for the use of tumor-specific T cells and antibodies in cancer therapy. Effective anti-tumor immunotherapy requires the identification of suitable target antigens. The expression of tumor-specific antigens has been extensively studied for most types of adult tumors. Pediatric patients should be excellent candidates for immunotherapy since their immune system is more potent and flexible as compared to that of adults. So far, these patients do not benefit enough from the progresses in cancer immunotherapy, and one of the reasons is the paucity of tumor-specific antigens identified on pediatric tumors. In this review we discuss the current status of cancer immunotherapy in children, focusing on the identification of tumor-specific antigens on pediatric solid tumors.
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Affiliation(s)
- J F M Jacobs
- Department of Pediatric Hemato-oncology, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
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Mirshahidi S, Kramer VG, Whitney JB, Essono S, Lee S, Dranoff G, Anderson KS, Ruprecht RM. Overlapping synthetic peptides encoding TPD52 as breast cancer vaccine in mice: prolonged survival. Vaccine 2009; 27:1825-33. [PMID: 19201387 PMCID: PMC4477950 DOI: 10.1016/j.vaccine.2009.01.089] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2008] [Revised: 01/13/2009] [Accepted: 01/16/2009] [Indexed: 12/21/2022]
Abstract
Peptide-based vaccines, one of several anti-tumor immunization strategies currently under investigation, can elicit both MHC Class I-restricted (CD8(+)) and Class II-restricted (CD4(+)) responses. However, the need to identify specific T-cell epitopes in the context of MHC alleles has hampered the application of this approach. We have tested overlapping synthetic peptides (OSP) representing a tumor antigen as a novel approach that bypasses the need for epitope mapping, since OSP contain all possible epitopes for both CD8(+) and CD4(+) T cells. Here we report that vaccination of inbred and outbred mice with OSP representing tumor protein D52 (TPD52-OSP), a potential tumor antigen target for immunotherapy against breast, prostate, and ovarian cancer, was safe and induced specific CD8(+) and CD4(+) T-cell responses, as demonstrated by development of specific cytotoxic T cell (CTL) activity, proliferative responses, interferon (IFN)-gamma production and CD107a/b expression in all mice tested. In addition, TPD52-OSP-vaccinated BALB/c mice were challenged with TS/A breast carcinoma cells expressing endogenous TPD52; significant survival benefits were noted in vaccine recipients compared to unvaccinated controls (p<0.001). Our proof-of-concept data demonstrate the safety and efficacy of peptide library-based cancer vaccines that obviates the need to identify epitopes or MHC backgrounds of the vaccinees. We show that an OSP vaccination approach can assist in the disruption of self-tolerance and conclude that our approach may hold promise for immunoprevention of early-stage cancers in a general population.
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Affiliation(s)
- Saied Mirshahidi
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
- Department of Medicine, Harvard Medical School, 44 Binney St, Boston, MA, 02115
| | - Victor G. Kramer
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
| | - James B. Whitney
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
- Department of Medicine, Harvard Medical School, 44 Binney St, Boston, MA, 02115
| | - Sosthène Essono
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
- Department of Medicine, Harvard Medical School, 44 Binney St, Boston, MA, 02115
| | - Sandra Lee
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
- Harvard School of Public Health, 44 Binney St, Boston, MA, 02115
| | - Glenn Dranoff
- Department of Medicine, Harvard Medical School, 44 Binney St, Boston, MA, 02115
- Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
| | - Karen S. Anderson
- Department of Medicine, Harvard Medical School, 44 Binney St, Boston, MA, 02115
- Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
| | - Ruth M. Ruprecht
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02115
- Department of Medicine, Harvard Medical School, 44 Binney St, Boston, MA, 02115
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12
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Jacobs JFM, Grauer OM, Brasseur F, Hoogerbrugge PM, Wesseling P, Gidding CE, van de Rakt MWMM, Figdor CG, Coulie PG, de Vries IJM, Adema GJ. Selective cancer-germline gene expression in pediatric brain tumors. J Neurooncol 2008; 88:273-80. [PMID: 18398575 PMCID: PMC2440921 DOI: 10.1007/s11060-008-9577-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2008] [Accepted: 03/26/2008] [Indexed: 01/09/2023]
Abstract
Cancer-germline genes (CGGs) code for immunogenic antigens that are present in various human tumors and can be targeted by immunotherapy. Their expression has been studied in a wide range of human tumors in adults. We measured the expression of 12 CGGs in pediatric brain tumors, to identify targets for therapeutic cancer vaccines. Real Time PCR was used to quantify the expression of genes MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MAGE-C2, NY-ESO-1 and GAGE-1,2,8 in 50 pediatric brain tumors of different histological subtypes. Protein expression was examined with immunohistochemistry. Fifty-five percent of the medulloblastomas (n = 11), 86% of the ependymomas (n = 7), 40% of the choroid plexus tumors (n = 5) and 67% of astrocytic tumors (n = 27) expressed one or more CGGs. Immunohistochemical analysis confirmed qPCR results. With exception of a minority of tumors, the overall level of CGG expression in pediatric brain tumors was low. We observed a high expression of at least one CGG in 32% of the samples. CGG-encoded antigens are therefore suitable targets in a very selected group of pediatric patients with a brain tumor. Interestingly, glioblastomas from adult patients expressed CGGs more often and at significantly higher levels compared to pediatric glioblastomas. This observation is in line with the notion that pediatric and adult glioblastomas develop along different genetic pathways.
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Affiliation(s)
- Joannes F M Jacobs
- Department of Pediatric Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Chen HS, Chen J, Cui DL, Zheng YY, Xu AH, Chen G, Jia LC. Effects of a Shuangling Fuzheng anticancer preparation on the proliferation of SGC-7901 cells and immune function in a cyclophosphamide-treated murine model. World J Gastroenterol 2007; 13:6575-80. [PMID: 18161930 PMCID: PMC4611299 DOI: 10.3748/wjg.v13.i48.6575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To study the inhibitory effects of a Shuangling Fuzheng anticancer preparation (SFAP) on the human gastric cancer cell line SGC-7901 in vitro as well as its immune-modulated effects in a cyclophosphamide-treated murine model.
METHODS: MTT experiments and immunocytochemistry ABC experiments were performed for detecting the proliferation of SGC-7901 cells in vitro and protein expression of c-myc. The staphylococcal protein A (SPA) rosette test was utilized for measuring the ratio of T-lymphocyte subsets from peripheral blood in a cyclophosphamide-treated murine model. Enzyme-linked immunosorbant assay (ELISA) was performed for measuring the levels of serum sIL-2R in treated mice, while immunoturbidimetry was used for measuring the levels of immunoglobulins (Ig).
RESULTS: SFAP (40-640 mg/L, 48 h) inhibited the proliferation of SGC-7901 cells, and a positive correlation was noted between inhibitory effects and dosage. At a dosage of 160-320 mg/L in cultured cells, the expression of c-myc was decreased. SFAP (50-200 mg/kg) increased the percentage of CD3+ and CD4+ T-lymphocytes, the ratio of CD4/CD8, and the contents of Ig such as IgM, IgG or IgA, but decreased the levels of serum sIL-2R in peripheral blood from cyclophosphamide-treated mice.
CONCLUSION: SFAP can inhibit the proliferation of SGC-7901 cells via the c-myc gene. In addition, SFAP can modulat the cellular and humoral immunity in cyclophosphamide-induced immunosuppressed mice.
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Tuyaerts S, Aerts JL, Corthals J, Neyns B, Heirman C, Breckpot K, Thielemans K, Bonehill A. Current approaches in dendritic cell generation and future implications for cancer immunotherapy. Cancer Immunol Immunother 2007; 56:1513-37. [PMID: 17503040 PMCID: PMC11030932 DOI: 10.1007/s00262-007-0334-z] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2007] [Accepted: 04/17/2007] [Indexed: 02/06/2023]
Abstract
The discovery of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, together with an improved insight in dendritic cell biology illustrating their key function in the immune system, have provided a rationale to initiate dendritic cell-based cancer immunotherapy trials. Nevertheless, dendritic cell vaccination is in an early stage, as methods for preparing tumor antigen presenting dendritic cells and improving their immunostimulatory function are continuously being optimized. In addition, recent improvements in immunomonitoring have emphasized the need for careful design of this part of the trials. Still, valuable proofs-of-principle have been obtained, which favor the use of dendritic cells in subsequent, more standardized clinical trials. Here, we review the recent developments in clinical DC generation, antigen loading methods and immunomonitoring approaches for DC-based trials.
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Affiliation(s)
- Sandra Tuyaerts
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
| | - Joeri L. Aerts
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
| | - Jurgen Corthals
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
| | - Bart Neyns
- Medical Oncology, Oncology Center, University Hospital Brussels, Free University Brussels, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Carlo Heirman
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
| | - Karine Breckpot
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
| | - Kris Thielemans
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
| | - Aude Bonehill
- Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium
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15
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Hamdy S, Elamanchili P, Alshamsan A, Molavi O, Satou T, Samuel J. Enhanced antigen-specific primary CD4+ and CD8+ responses by codelivery of ovalbumin and toll-like receptor ligand monophosphoryl lipid A in poly(D,L-lactic-co-glycolic acid) nanoparticles. J Biomed Mater Res A 2007; 81:652-62. [PMID: 17187395 DOI: 10.1002/jbm.a.31019] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The purpose of this research was to investigate the use of biodegradable poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA-NP) as a vaccine delivery system to codeliver antigen, ovalbumin (OVA) along with monophosphoryl lipid A (MPLA) as adjuvant for induction of potent CD4(+) and CD8(+) T cell responses. The primary CD4(+) T responses to OVA/MPLA NP were investigated using OVA-specific T cells from DO11.10 transgenic mice. Following adoptive transfer of these cells, mice were immunized s.c. by NP formulations. For assessing the CD8(+) responses, bone marrow derived dendritic cells (DCs) were pulsed with different OVA formulations, then, cocultured with CD8(+) T cells from OT-1 mice. T cell proliferation/activation and IFN-gamma secretion profile have been examined. Particulate delivery of OVA and MPLA to the DCs lead to markedly increase in in vitro CD8(+) T cell T cell proliferative responses (stimulation index >3000) and >13-folds increase in in vivo clonal expanded CD4(+) T cells. The expanded T cells were capable of cytokine secretion and expressed an activation and memory surface phenotype (CD62L(lo), CD11a(hi), and CD44(hi)). Codelivery of antigen and MPLA in PLGA-NP offers an effective method for induction of potent antigen specific CD4(+) and CD8(+) T cell responses.
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Affiliation(s)
- Samar Hamdy
- Faculty of Pharmacy and Pharmaceutical Sciences, 3133 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2N8
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16
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Lepage S, Lapointe R. Melanosomal targeting sequences from gp100 are essential for MHC class II-restricted endogenous epitope presentation and mobilization to endosomal compartments. Cancer Res 2006; 66:2423-32. [PMID: 16489049 DOI: 10.1158/0008-5472.can-05-2516] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
CD4+ T lymphocytes play an important role in CD8+ T cell-mediated responses against tumors. Considering that approximately 20% of melanomas express MHC class II, it is plausible that concomitant presentation by MHC class I and class II shapes positive (helper T cells) or negative (regulatory T cells) antitumor responses. Interestingly, gp100, a melanoma antigen, can be presented by both MHC class I and class II when expressed endogenously, suggesting that it can reach endosomal/MHC class II compartments (MIIC). Here, we showed that gp100 putative NH2-terminal signal sequence and the last 70 residues in COOH terminus are essential for MIIC localization and MHC class II presentation. Confocal microscopy analyses confirmed that gp100 was localized in LAMP-1+/HLA-DR+ endosomal/MIIC. Gp100 targeting sequences were characterized by deleting different sections in the COOH terminus (last 70 residues). Transfection in 293T cells, expressing MHC class I and class II molecules, revealed that specific deletions in COOH terminus resulted in decreased MHC class II presentation, without effects on class I presentation, suggesting a role in MIIC trafficking for these deleted sections. Then, we used these gp100 targeting sequences to mobilize green fluorescent protein to endosomal compartments and to allow MHC class II and class I presentation of minimal endogenous epitopes. We conclude that these specific sequences are MIIC-targeting motifs, which could be included in expression cassettes for endogenously expressed tumor or viral antigens for MHC class II and class I presentation and optimize in vivo T-cell responses or as an in vitro tool for characterization of new MHC class II epitopes.
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Affiliation(s)
- Stéphanie Lepage
- Research Centre, Centre Hospitalier de l'Université de Montréal, Hôpital Notre Dame, Université de Montréal and Institut du Cancer de Montréal, Montréal, Québec, Canada
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17
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Jacobs JFM, Brasseur F, Hulsbergen-van de Kaa CA, van de Rakt MWMM, Figdor CG, Adema GJ, Hoogerbrugge PM, Coulie PG, de Vries IJM. Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR. Int J Cancer 2006; 120:67-74. [PMID: 17019710 DOI: 10.1002/ijc.22118] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Cancer-germline genes (CGGs) code for immunogenic antigens that are present on various human tumors but not on normal tissues. The importance of CGGs in cancer immunotherapy has led to detailed studies of their expression in a range of human tumors. We measured the levels of expression of 12 CGGs in various pediatric solid tumors to identify targets for therapeutic cancer vaccines. Quantitative real-time PCR (qPCR) was used to measure the expression of 8 MAGE genes and of genes LAGE-2/NY-ESO-1 and GAGE-1, 2, 8 in 9 osteosarcomas, 10 neuroblastomas, 12 rhabdomyosarcomas and 18 Ewing's sarcomas. Nine tumors were also examined by immunohistochemistry with monoclonal antibodies specific for the MAGE-A1, MAGE-A4 and NY-ESO-1 proteins. All osteosarcoma and 80% of neuroblastoma samples expressed several CGGs at high levels. Six of 12 rhabdomyosarcomas and 11 of 18 Ewing's sarcomas expressed at least one CGG. Immunohistochemistry data correlated well with qPCR results and showed a homogeneous protein distribution pattern in most positive tumors. No correlation was found between the levels of CGG expression in the tumors and clinicopathological parameters of the patients. Pediatric solid tumors express several CGGs, which encode antigens that could be targeted in therapeutic vaccination trials. Several CGGs of the MAGE, GAGE and LAGE families are coexpressed in a large proportion of osteosarcoma and neuroblastoma samples. Some rhabdomyosarcomas express several of these genes at high levels. Ewing's sarcomas have an overall low CGG expression.
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Affiliation(s)
- Joannes F M Jacobs
- Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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18
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Jeras M, Bergant M, Repnik U. In vitro preparation and functional assessment of human monocyte-derived dendritic cells—potential antigen-specific modulators of in vivo immune responses. Transpl Immunol 2005; 14:231-44. [PMID: 15982568 DOI: 10.1016/j.trim.2005.03.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2005] [Indexed: 02/02/2023]
Abstract
Dendritic cells (DCs) are highly specialized professional antigen presenting cells that have a potent capacity for stimulating naïve, memory and effector T-cells. They are located in lymphoid organs as well as in almost all nonlymphoid tissues. Immature DCs, residing in the host microenvironment, respond to danger signals with maturation, a differentiation process along which they acquire the ability to direct the extent and the type of primary immune responses according to the type of danger perceived. In this review we present some of our approaches and experiences regarding the isolation of human monocytes from peripheral blood and the in vitro preparation of, first, immature and then mature DCs by applying several maturation factors: bacterial lipopolysaccharide (LPS), a defined mixture of recombinant pro-inflammatory cytokines, monocyte conditioned medium (MCM) and TNF-alpha alone. The assessment of DC phenotypes and their functional capabilities as well as some of the techniques used for tumour associated antigen loading are also presented. The results of such studies represent a basis for optimal in vitro preparation of DCs, which could be clinically used to modulate immune responses in cancer, autoimmune diseases and in the planned onset of tolerance to disparate major histocompatibilty complex (MHC) antigens prior to tissue or organ transplantation.
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Affiliation(s)
- Matjaz Jeras
- Blood Transfusion Centre of Slovenia, Tissue Typing Center, Slajmerjeva 6, SI-1000 Ljubljana, Slovenia.
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19
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Warrino DE, Olson WC, Scarrow MI, D'Ambrosio-Brennan LJ, Guido RS, Da Silva DM, Kast WM, Storkus WJ. Human Papillomavirus L1L2-E7 Virus-Like Particles Partially Mature Human Dendritic Cells and Elicit E7-Specific T-Helper Responses From Patients With Cervical Intraepithelial Neoplasia or Cervical Cancer In Vitro. Hum Immunol 2005; 66:762-72. [PMID: 16112023 DOI: 10.1016/j.humimm.2005.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2004] [Revised: 04/11/2005] [Accepted: 04/14/2005] [Indexed: 10/25/2022]
Abstract
We evaluated the ability of autologous dendritic cells (DC) pulsed with recombinant human papillomavirus 16 L1L2-E7 virus-like particles (VLPs) to stimulate E7-specific CD4+ T-cell responses from normal donors and patients with cervical intraepithelial neoplasia lesions or cervical carcinoma in vitro. Exposure to VLPs partially matured DCs, as evidenced by upregulated expression of costimulatory and major histocompatibility complex molecules and the reduced capacity of treated DCs to process exogenous antigens. However, VLP treatment failed to promote strong expression of the CD83 or CCR7 markers or to modulate interleukin-12p70 secretion, indicators of terminal DC maturation. Notably, both normal donor- and patient-derived DCs behaved similarly after exposure to VLPs. A single round of in vitro stimulation of CD4+ T cells with DCs exposed to L1L2-E7 VLPs promoted specific anti-E7 responses in the majority of donors. In particular, DCs exposed to VLPs effectively stimulated type 1 biased E7-specific CD4+ T-cell responses in patients with premalignant cervical intraepithelial neoplasia I-III lesions, but type 2 or Treg biased responses in patients with cervical cancer. Given the high rate of CD4+ T-cell responses (14 [93%] of 15 patients) against DC-L1L2-E7 VLP stimulation, this vaccine modality could serve as a foundation for developing a general treatment option for patients with human papillomavirus 16-associated malignancies.
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Affiliation(s)
- Dominic E Warrino
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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20
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Willemsen R, Ronteltap C, Heuveling M, Debets R, Bolhuis R. Redirecting human CD4+ T lymphocytes to the MHC class I-restricted melanoma antigen MAGE-A1 by TCR alphabeta gene transfer requires CD8alpha. Gene Ther 2005; 12:140-6. [PMID: 15496961 DOI: 10.1038/sj.gt.3302388] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has demonstrated its effectiveness in the eradication of cancer and virally infected cells. Clinical trails and in vitro studies have focused on CD8+ cytotoxic T-cell receptor (TCR) alphabeta lymphocytes since these cells directly kill virally infected- and tumor cells after antigen-specific recognition via their TCR alphabeta. However, increasing evidence suggests that induction of sustained immunity against cancer and viral infections depends on the presence of tumor- or virus-specific CD4+ T lymphocytes, which are restricted by MHC class II. Here, we show that these MHC class II-restricted CD4+ T lymphocytes can efficiently be redirected to MHC class I-restricted tumor cells by retroviral introduction of an HLA-A1/MAGE-A1-specific chimeric two-chain TCR ValphaCalphazeta/VbetaCbetazeta (tcTCR/zeta). However, TCR-transduced CD4+ T lymphocytes were only able to specifically bind to HLA-A1/MAGE-A1 complexes and respond to HLA-A1+/MAGE-A1+ melanoma cells when the CD8alpha gene was cointroduced. These CD4+/CD8alpha+/TCR(POS) T lymphocytes produce IFN-gamma, TNFalpha and IL-2 when specifically stimulated via the introduced TCR with immobilized HLA-A1/MAGE-A1 complexes or HLA-A1+/MAGE-A1+ melanoma cells. Furthermore, introduction of the CD8alpha gene into TCR(POS) T lymphocytes rendered these T lymphocytes cytotoxic for HLA-A1+/MAGE-A1+ melanoma cells. These results demonstrate that human CD4+ T lymphocytes when genetically grafted with an HLA-A1/MAGE-A1-specific TCR and CD8alpha are induced to kill and produce cytokines upon specific interaction with the relevant melanoma cells. Hence, CD4+ T lymphocytes, in addition to CD8+ T lymphocytes, may be critical effector cells for adoptive immuno-gene therapy to generate a sustained tumor-specific immune response in cancer patients.
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Affiliation(s)
- R Willemsen
- Laboratory of Tumor Immunology, Department of Medical Oncology, ErasmusMC-Daniel den Hoed, Rotterdam, Netherlands
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21
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Pan B, Cheng T, Nan KJ, Qiu GQ, Sun XC. Effect of Fuzheng Yiliu decoction combined with chemotherapy on patients with intermediate and late stage gastrointestinal cancer. World J Gastroenterol 2005; 11:439-42. [PMID: 15637764 PMCID: PMC4205358 DOI: 10.3748/wjg.v11.i3.439] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [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 investigate the therapeutic effects of Fuzheng Yiliu (strengthening the body resistance to inhibit tumor) decoction combined with chemotherapy on the patients with intermediate and late stage gastrointestinal cancer.
METHODS: Sixty patients were randomly divided into treatment group (chemotherapy combined with Fuzheng Yiliu decoction) and control group (chemotherapy alone). Four indexes, including the tumor recent remission rate (RR), the change of main symptoms, the toxic and side effects caused by chemotherapy and the change of performance status, were observed in the patients. Peripheral blood contents of CD3+, CD4+, CD8+ cells, CD4+/CD8+ and soluble interleukin-2 receptor (sIL-2R) were tested before and after treatment and the values were compared with those of healthy peoples.
RESULTS: The improving rate of main symptoms (69.6%) and performance status (56.7%) were significantly higher in the treatment group than in the control group (34.8%, 26.7%, P<0.05). The occurrence rates of grade II toxic and side-effects on both bone marrow (13.3%) and digestive tract (30%) were lower in the treatment group compared to the control group (36.7%, 63.3%, P<0.05). Before treatment, the proportion of CD3+, CD4+ and CD4+/CD8+ decreased and the proportion of CD8+ and sIL-2R raised markedly both in the control group and treatment group as compared to the healthy people. After treatment, that increased of CD3+, CD4+, CD4+/CD8+ increased (62.25±10.01% vs 68.31±9.72%, 36.83±10.44% vs 42.6±9.62%, 1.24±0.65 vs 1.66±0.85, P<0.05) and the values of CD8+ and sIL-2R decreased obviously (33.06±7.69% vs 29.24±6.25%, 588.23±216.86 U/mL vs 475.87±211.36 U/mL, P<0.05) in the treatment group, whereas these values were opposite in the control group (64.22±6.91% vs 60.63±5.75%, 35.62±7.49% vs 31.53±5.53%, 32.95±8.28% vs 37.14±7.48%, 1.17±0.43 vs 0.94±0.43, 573.63±214.32 U/mL vs 692.17±221.33 U/mL, P<0.05).
CONCLUSION: Fuzheng Yiliu decoction can enhance therapeutic effects of chemotherapy on malignant gastrointestinal tumor, and also reduce the toxic and side effects on bone marrow and digestive tract, thereby improving the quality of life and cellular immunity in patients with malignant gastrointestinal tumor.
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Affiliation(s)
- Bin Pan
- Department of Physiology, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
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22
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Markiewicz MA, Kast WM. Progress in the Development of Immunotherapy of Cancer Using Ex Vivo-Generated Dendritic Cells Expressing Multiple Tumor Antigen Epitopes. Cancer Invest 2004; 22:417-34. [PMID: 15493363 DOI: 10.1081/cnv-200029072] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immunotherapy with tumor-associated antigen-pulsed, ex vivo-generated dendritic cells (DCs) is a promising approach for the treatment of cancer that has shown efficacy in animal models and is now being tested in the clinic. The majority of studies performed to date make use of a single tumor-associated epitope. However, because of the high rate of mutation in tumor cells allowing for loss of expression of a single antigen, it is likely that use of multiple antigenic epitopes will induce a broader, longer-lasting, and effective tumor-specific immune response. Multiple vehicles for loading DCs with multiple antigenic epitopes are under investigation to determine the most effective method for vaccination, with many of these methods showing promise. These loading methods, as well as other critical considerations for making DC vaccination as efficacious as possible, are discussed in this article.
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MESH Headings
- Antigen Presentation
- Antigens, Neoplasm/immunology
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/therapeutic use
- Cell Fusion
- Cells, Cultured/immunology
- Cells, Cultured/transplantation
- Clinical Trials as Topic
- DNA, Neoplasm/administration & dosage
- DNA, Neoplasm/genetics
- DNA, Neoplasm/immunology
- Dendritic Cells/immunology
- Dendritic Cells/transplantation
- Epitopes/immunology
- Gene Transfer Techniques
- Humans
- Hybrid Cells/transplantation
- Immunotherapy, Adoptive
- Neoplasm Proteins/immunology
- Neoplasms/immunology
- Neoplasms/pathology
- Neoplasms/therapy
- Peptide Fragments/immunology
- RNA, Neoplasm/administration & dosage
- T-Lymphocytes, Cytotoxic/immunology
- Vaccines, DNA/therapeutic use
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Affiliation(s)
- Mary A Markiewicz
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089-2821, USA
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23
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Eiben GL, da Silva DM, Fausch SC, Le Poole IC, Nishimura MI, Kast WM. Cervical cancer vaccines: recent advances in HPV research. Viral Immunol 2003; 16:111-21. [PMID: 12828864 DOI: 10.1089/088282403322017866] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Carcinomas of the anogenital tract, particularly cancer of the cervix, account for almost 12% of all cancers in women, and so represent the second most frequent gynecological malignancy in the world (48). It is well established that chronic infection of cervical epithelium by human papillomaviruses (HPV) is necessary for the development of cervical cancer. In fact, HPV DNA has been demonstrated in more than 99.7% of cervical cancer biopsy specimens, with high-risk HPV16 and HPV18 sequences being most prevalent (45,73). Therefore, an effective vaccine that would mount an immune response against HPV-related proteins might contribute to the prevention or elimination of HPV expressing lesions. This review will concentrate on the most recent advances in vaccine-mediated prevention and immunotherapy of HPV-induced cervical cancer, including presentations from the 20(th) International HPV Conference held in October 2002 in Paris.
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Affiliation(s)
- Gretchen L Eiben
- Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois 60153, USA
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