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Blander JM, Yee Mon KJ, Jha A, Roycroft D. The show and tell of cross-presentation. Adv Immunol 2023; 159:33-114. [PMID: 37996207 DOI: 10.1016/bs.ai.2023.08.002] [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] [Indexed: 11/25/2023]
Abstract
Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the context of viral or non-viral infection and cancer. DCs have an extensive network of endovesicular pathways that orchestrate the biogenesis of an ideal cross-presentation compartment where processed antigen, MHC-I molecules, and the MHC-I peptide loading machinery all meet. As a central conveyor of information to CD8 T cells, cross-presentation allows cross-priming of T cells which carry out robust adaptive immune responses for tumor and viral clearance. Cross-presentation can be canonical or noncanonical depending on the functional status of the transporter associated with antigen processing (TAP), which in turn influences the vesicular route of MHC-I delivery to internalized antigen and the cross-presented repertoire of peptides. Because TAP is a central node in MHC-I presentation, it is targeted by immune evasive viruses and cancers. Thus, understanding the differences between canonical and noncanonical cross-presentation may inform new therapeutic avenues against cancer and infectious disease. Defects in cross-presentation on a cellular and genetic level lead to immune-related disease progression, recurrent infection, and cancer progression. In this chapter, we review the process of cross-presentation beginning with the DC subsets that conduct cross-presentation, the signals that regulate cross-presentation, the vesicular trafficking pathways that orchestrate cross-presentation, the modes of cross-presentation, and ending with disease contexts where cross-presentation plays a role.
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Affiliation(s)
- J Magarian Blander
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, United States; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, United States; Immunology and Microbial Pathogenesis Programs, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, United States.
| | - Kristel Joy Yee Mon
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
| | - Atimukta Jha
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
| | - Dylan Roycroft
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, United States; Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, United States
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Park BR, Bommireddy R, Chung DH, Kim KH, Subbiah J, Jung YJ, Bhatnagar N, Pack CD, Ramachandiran S, Reddy SJC, Selvaraj P, Kang SM. Hemagglutinin virus-like particles incorporated with membrane-bound cytokine adjuvants provide protection against homologous and heterologous influenza virus challenge in aged mice. Immun Ageing 2023; 20:20. [PMID: 37170231 PMCID: PMC10173218 DOI: 10.1186/s12979-023-00344-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 04/24/2023] [Indexed: 05/13/2023]
Abstract
BACKGROUND Current influenza vaccines deliver satisfactory results in young people but are less effective in the elderly. Development of vaccines for an ever-increasing aging population has been an arduous challenge due to immunosenescence that impairs the immune response in the aged, both quantitatively and qualitatively. RESULTS To potentially enhance vaccine efficacy in the elderly, we investigated the immunogenicity and cross-protection of influenza hemagglutinin virus-like particles (HA-VLP) incorporated with glycosylphosphatidylinositol (GPI)-anchored cytokine-adjuvants (GPI-GM-CSF and GPI-IL-12) via protein transfer in aged mice. Lung viral replication against homologous and heterologous influenza viruses was significantly reduced in aged mice after vaccination with cytokine incorporated VLPs (HA-VLP-Cyt) in comparison to HA-VLP alone. Enhanced IFN-γ+CD4+ and IFN-γ+CD8+ T cell responses were also observed in aged mice immunized with HA-VLP-Cyt when compared to HA-VLP alone. CONCLUSIONS Cytokine-adjuvanted influenza HA-VLP vaccine induced enhanced protective response against homologous influenza A virus infection in aged mice. Influenza HA-VLP vaccine with GPI-cytokines also induced enhanced T cell responses correlating with better protection against heterologous infection in the absence of neutralizing antibodies. The results suggest that a vaccination strategy using cytokine-adjuvanted influenza HA-VLPs could be used to enhance protection against influenza A virus in the elderly.
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Affiliation(s)
- Bo Ryoung Park
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Ramireddy Bommireddy
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - David Hyunjung Chung
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Ki-Hye Kim
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Jeeva Subbiah
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Yu-Jin Jung
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | - Noopur Bhatnagar
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
| | | | | | | | - Periasamy Selvaraj
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Sang-Moo Kang
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA.
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Bommireddy R, Stone S, Bhatnagar N, Kumari P, Munoz LE, Oh J, Kim KH, Berry JTL, Jacobsen KM, Jaafar L, Naing SH, Blackerby AN, der Gaag TV, Wright CN, Lai L, Pack CD, Ramachandiran S, Suthar MS, Kang SM, Kumar M, Reddy SJC, Selvaraj P. Influenza Virus-like Particle-Based Hybrid Vaccine Containing RBD Induces Immunity against Influenza and SARS-CoV-2 Viruses. Vaccines (Basel) 2022; 10:944. [PMID: 35746552 PMCID: PMC9230705 DOI: 10.3390/vaccines10060944] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/28/2022] [Accepted: 06/06/2022] [Indexed: 02/05/2023] Open
Abstract
Several approaches have produced an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since millions of people are exposed to influenza virus and SARS-CoV-2, it is of great interest to develop a two-in-one vaccine that will be able to protect against infection of both viruses. We have developed a hybrid vaccine for SARS-CoV-2 and influenza viruses using influenza virus-like particles (VLP) incorporated by protein transfer with glycosylphosphatidylinositol (GPI)-anchored SARS-CoV-2 RBD fused to GM-CSF as an adjuvant. GPI-RBD-GM-CSF fusion protein was expressed in CHO-S cells, purified and incorporated onto influenza VLPs to develop the hybrid vaccine. Our results show that the hybrid vaccine induced a strong antibody response and protected mice from both influenza virus and mouse-adapted SARS-CoV-2 challenges, with vaccinated mice having significantly lower lung viral titers compared to naive mice. These results suggest that a hybrid vaccine strategy is a promising approach for developing multivalent vaccines to prevent influenza A and SARS-CoV-2 infections.
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Affiliation(s)
- Ramireddy Bommireddy
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| | - Shannon Stone
- Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA; (S.S.); (P.K.); (M.K.)
| | - Noopur Bhatnagar
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Pratima Kumari
- Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA; (S.S.); (P.K.); (M.K.)
| | - Luis E. Munoz
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| | - Judy Oh
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Ki-Hye Kim
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Jameson T. L. Berry
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
| | - Kristen M. Jacobsen
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Lahcen Jaafar
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Swe-Htet Naing
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Allison N. Blackerby
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Tori Van der Gaag
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Chloe N. Wright
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Lilin Lai
- Department of Pediatrics, Emory Vaccine Center, Yerkes Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA; (L.L.); (M.S.S.)
| | - Christopher D. Pack
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Sampath Ramachandiran
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Mehul S. Suthar
- Department of Pediatrics, Emory Vaccine Center, Yerkes Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA; (L.L.); (M.S.S.)
| | - Sang-Moo Kang
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA; (N.B.); (J.O.); (K.-H.K.); (S.-M.K.)
| | - Mukesh Kumar
- Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA; (S.S.); (P.K.); (M.K.)
| | - Shaker J. C. Reddy
- Metaclipse Therapeutics Corporation, Atlanta, GA 30340, USA; (K.M.J.); (L.J.); (S.-H.N.); (A.N.B.); (T.V.d.G.); (C.N.W.); (C.D.P.); (S.R.); (S.J.C.R.)
| | - Periasamy Selvaraj
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; (R.B.); (L.E.M.); (J.T.L.B.)
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Salem A, Alotaibi M, Mroueh R, Basheer HA, Afarinkia K. CCR7 as a therapeutic target in Cancer. Biochim Biophys Acta Rev Cancer 2020; 1875:188499. [PMID: 33385485 DOI: 10.1016/j.bbcan.2020.188499] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/24/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023]
Abstract
The CCR7 chemokine axis is comprised of chemokine ligand 21 (CCL21) and chemokine ligand 19 (CCL19) acting on chemokine receptor 7 (CCR7). This axis plays two important but apparently opposing roles in cancer. On the one hand, this axis is significantly engaged in the trafficking of a number of effecter cells involved in mounting an immune response to a growing tumour. This suggests therapeutic strategies which involve potentiation of this axis can be used to combat the spread of cancer. On the other hand, the CCR7 axis plays a significant role in controlling the migration of tumour cells towards the lymphatic system and metastasis and can thus contribute to the expansion of cancer. This implies that therapeutic strategies which involve decreasing signaling through the CCR7 axis would have a beneficial effect in preventing dissemination of cancer. This dichotomy has partly been the reason why this axis has not yet been exploited, as other chemokine axes have, as a therapeutic target in cancer. Recent report of a crystal structure for CCR7 provides opportunities to exploit this axis in developing new cancer therapies. However, it remains unclear which of these two strategies, potentiation or antagonism of the CCR7 axis, is more appropriate for cancer therapy. This review brings together the evidence supporting both roles of the CCR7 axis in cancer and examines the future potential of each of the two different therapeutic approaches involving the CCR7 axis in cancer.
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Affiliation(s)
- Anwar Salem
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom
| | - Mashael Alotaibi
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom
| | - Rima Mroueh
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom
| | - Haneen A Basheer
- Faculty of Pharmacy, Zarqa University, PO Box 132222, Zarqa 13132, Jordan
| | - Kamyar Afarinkia
- Institute of Cancer Therapeutics, University of Bradford; Bradford BD7 1DP, United Kingdom.
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Simula L, Pacella I, Colamatteo A, Procaccini C, Cancila V, Bordi M, Tregnago C, Corrado M, Pigazzi M, Barnaba V, Tripodo C, Matarese G, Piconese S, Campello S. Drp1 Controls Effective T Cell Immune-Surveillance by Regulating T Cell Migration, Proliferation, and cMyc-Dependent Metabolic Reprogramming. Cell Rep 2019; 25:3059-3073.e10. [PMID: 30540939 PMCID: PMC6302735 DOI: 10.1016/j.celrep.2018.11.018] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 08/01/2018] [Accepted: 11/01/2018] [Indexed: 01/09/2023] Open
Abstract
Mitochondria are key players in the regulation of T cell biology by dynamically responding to cell needs, but how these dynamics integrate in T cells is still poorly understood. We show here that the mitochondrial pro-fission protein Drp1 fosters migration and expansion of developing thymocytes both in vitro and in vivo. In addition, we find that Drp1 sustains in vitro clonal expansion and cMyc-dependent metabolic reprogramming upon activation, also regulating effector T cell numbers in vivo. Migration and extravasation defects are also exhibited in Drp1-deficient mature T cells, unveiling its crucial role in controlling both T cell recirculation in secondary lymphoid organs and accumulation at tumor sites. Moreover, the observed Drp1-dependent imbalance toward a memory-like phenotype favors T cell exhaustion in the tumor microenvironment. All of these findings support a crucial role for Drp1 in several processes during T cell development and in anti-tumor immune-surveillance.
The pro-fission protein Drp1 sustains correct thymocyte maturation Drp1 promotes T cell metabolic reprogramming and expansion upon activation Drp1 allows efficient T cell extravasation from blood and infiltration into tumors An optimal T cell anti-tumor response requires Drp1
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Affiliation(s)
- Luca Simula
- Department of Biology, University of Rome Tor Vergata, Rome, Italy; IRCCS, Fondazione Santa Lucia, Rome, Italy
| | - Ilenia Pacella
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Alessandra Colamatteo
- Department of Molecular Medicine and Biotechnologies, University of Naples "Federico II," Naples, Italy
| | - Claudio Procaccini
- IRCCS, Fondazione Santa Lucia, Rome, Italy; Institute of Experimental Oncology and Endocrinology, National Research Council (IEOS-CNR), Naples, Italy
| | - Valeria Cancila
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, Italy
| | - Matteo Bordi
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Claudia Tregnago
- Department of Women and Child Health, Haematology-Oncology Clinic and Lab, University of Padova, Padova, Italy
| | - Mauro Corrado
- Max Planck Institute of Immunology and Epigenetics, Freiburg im Breisgau, Germany
| | - Martina Pigazzi
- Department of Women and Child Health, Haematology-Oncology Clinic and Lab, University of Padova, Padova, Italy
| | - Vincenzo Barnaba
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, Italy
| | - Giuseppe Matarese
- Department of Molecular Medicine and Biotechnologies, University of Naples "Federico II," Naples, Italy; Institute of Experimental Oncology and Endocrinology, National Research Council (IEOS-CNR), Naples, Italy
| | - Silvia Piconese
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Silvia Campello
- Department of Biology, University of Rome Tor Vergata, Rome, Italy; IRCCS, Fondazione Santa Lucia, Rome, Italy.
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Zhong M, Zhong C, Cui W, Wang G, Zheng G, Li L, Zhang J, Ren R, Gao H, Wang T, Li X, Che J, Gohda E. Induction of tolerogenic dendritic cells by activated TGF-β/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells. BMC Cancer 2019; 19:439. [PMID: 31088527 PMCID: PMC6515680 DOI: 10.1186/s12885-019-5670-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 05/02/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Dendritic cells (DCs) alter their role from being immunostimulatory to immunosuppressive at advanced stages of tumor progression, but the influence of cancer stem cells (CSCs) and their secreted factors on generation and phenotypic change of DCs is unknown. Retinoic acid-inducible gene I (RIG-I) plays a role in regulation of other cellular processes including leukemic stemness besides its antiviral function. METHODS Short hairpin RNA-mediated gene silencing was employed to generate stable RIG-I-knocked-down human hepatocellular carcinoma (HCC) cell lines. Expression levels of genes and proteins in spheres of those HCC cells were determined by quantitative real-time PCR and Western bot, respectively. Levels of secreted cytokines were measured by ELISA. The surface molecule expression levels of DCs were analyzed using flow cytometry. The ability of DCs to induce proliferation of T cells was assessed by a mixed lymphocyte reaction (MLR) assay. RESULTS RIG-I-knocked-down HCC cells showed upregulated expression of stem cell marker genes, enhanced secretion of factors suppressing in vitro generation of DCs into the conditioned medium (CM), and induction of a phenotype of tumor-infiltrating DCs (TIDCs) with low levels of DC markers in their tumors in nude mice. Those DCs and TIDCs showed reduced MLR, indicating RIG-I deficiency-induced immunotolerance. The RIG-I-deficient HCC cells secreted more TGF-β1 than did reference cells. The tumors formed after injection of RIG-I-deficient HCC cells had higher TGF-β1 contents than did tumors derived from control cells. DC generation and MLR suppressed by the CM of RIG-I-deficient HCC cells were restored by an anti-TGF-β1 antibody. TGF-β1-induced phosphorylation of Smad2 and Akt was enhanced in RIG-I-deficient HCC spheres, knockdown of AKT gene expression abolishing the augmentation of TGF-β1-induced Smad2 phosphorylation. Akt and p-Akt were co-immunoprecipitated with Smad2 in cytoplasmic proteins of RIG-I-deficient spheres but not in those of control spheres, the amounts of co-immunoprecipitated Akt and p-Akt being increased by TGF-β stimulation. CONCLUSIONS Our results demonstrate that RIG-I deficiency in HCC cells induced their stemness, enhanced secretion and signaling of TGF-β1, tolerogenic TIDCs and less generation of DCs, and the results suggest involvement of TGF-β1 in those RIG-I deficiency-induced tolerogenic changes and involvement of CSCs in DC-mediated immunotolerance.
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Affiliation(s)
- Ming Zhong
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Cheng Zhong
- Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Wen Cui
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Guanghui Wang
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Gongpu Zheng
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Li Li
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Jing Zhang
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Rujing Ren
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | - Huijei Gao
- Institute of Tumor Pharmacology, Jining Medical College, Xueyuan Road 669, Rizhao, 276826 China
| | | | - Xin Li
- People’s Hospital of Rizhao, Rizhao, China
| | - Jiantu Che
- S&V Biological Science and Technology Co., Ltd., Beijing, China
| | - Eiichi Gohda
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Dong Y, Ma T, Zhang X, Ying Q, Han M, Zhang M, Yang R, Li Y, Wang F, Liu R, Wu X. Incorporation of CD40 ligand or granulocyte-macrophage colony stimulating factor into Hantaan virus (HTNV) virus-like particles significantly enhances the long-term immunity potency against HTNV infection. J Med Microbiol 2019; 68:480-492. [PMID: 30657443 DOI: 10.1099/jmm.0.000897] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Hantavirus infections cause severe haemorrhagic fever with renal syndrome (HFRS) in humans and are associated with high fatality rates. In 2017, numerous outbreaks were reported in China and Germany. This represents a significant public-healthcare issue with no effective HFRS vaccines that offer a long-term immune response. In this study, we investigated the long-term humoral and cellular immune responses and protective immunity of Hantaan virus (HTNV) granulocyte-macrophage colony stimulating factor (GM-CSF) and CD40 ligand (CD40L) virus-like particles (VLPs) in mice. METHODOLOGY GM-CSF and CD40L VLPs were constructed via co-transfection of pCI-S and pCI-M-CD40L, and pCI-S and pCI-M-GM-CSF, into dihydrofolatereductase (dhfr)-deficient Chinese hamster ovary cells, respectively. Mice were immunized with HTNV VLPs 2 weeks apart. The animals were challenged 6 months after immunization. Specific and neutralizing antibodies were assessed by ELISA; IFN-γ was measured by enzyme-linked immunospot (ELISpot) assay and effectiveness by cytotoxic T lymphocyte (CTL) cytotoxicity assays. Nucleic acid loads of HTNV were tested by quantitative real-time PCR and viral antigen was detected via indirect ELISA. Pathological alterations were detected via haematoxylin-eosin staining. RESULTS GM-CSF and CD40L VLPs provided stable, long-term protection with a high titre of neutralizing antibody in mice 6 months after immunization. Furthermore, VLPs increased HTNV-specific cellular immune responses via higher expression of IFN-γ and CTL responses. HTNV challenge assay results showed long-term protection against HFRS. No significant pathological alteration was observed in the organs of mice after immunization. CONCLUSION This is, to the best of our knowledge, the first report demonstrating the long-term potency of HTNV VLP vaccines against HTNV infection and offers new insights into HTNV vaccine development.
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Affiliation(s)
- Yuhang Dong
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
| | - Tiejun Ma
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
| | - Xiaoxiao Zhang
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
| | - Qikang Ying
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
| | - Mingwei Han
- 2No. 1 Cadet Brigade, Fourth Military Medical University, Xi'an, PR China
| | - Muqi Zhang
- 2No. 1 Cadet Brigade, Fourth Military Medical University, Xi'an, PR China
| | - Rongjin Yang
- 2No. 1 Cadet Brigade, Fourth Military Medical University, Xi'an, PR China
| | - Yuan Li
- 2No. 1 Cadet Brigade, Fourth Military Medical University, Xi'an, PR China
| | - Fang Wang
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
| | - Rongrong Liu
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
| | - Xingan Wu
- 1Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, PR China
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Interplay between dendritic cells and cancer cells. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 348:179-215. [DOI: 10.1016/bs.ircmb.2019.07.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Pacella I, Cammarata I, Focaccetti C, Miacci S, Gulino A, Tripodo C, Ravà M, Barnaba V, Piconese S. Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth. Cancer Immunol Res 2018; 6:953-964. [DOI: 10.1158/2326-6066.cir-17-0713] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 05/16/2018] [Accepted: 06/13/2018] [Indexed: 11/16/2022]
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Soliman H, Mediavilla-Varela M, Antonia SJ. A GM-CSF and CD40L bystander vaccine is effective in a murine breast cancer model. BREAST CANCER-TARGETS AND THERAPY 2015; 7:389-97. [PMID: 26719725 PMCID: PMC4687618 DOI: 10.2147/bctt.s89563] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Background There is increasing interest in using cancer vaccines to treat breast cancer patients in the adjuvant setting to prevent recurrence in high risk situations or in combination with other immunomodulators in the advanced setting. Current peptide vaccines are limited by immunologic compatibility issues, and engineered autologous cellular vaccines are difficult to produce on a large scale. Using standardized bystander cell lines modified to secrete immune stimulating adjuvant substances can greatly enhance the ability to produce immunogenic cellular vaccines using unmodified autologous cells or allogeneic medical grade tumor cell lines as targets. We investigated the efficacy of a cellular vaccine using B78H1 bystander cell lines engineered to secrete granulocyte macrophage-colony stimulating factor and CD40 ligand (BCG) in a murine model of breast cancer. Methods Five-week-old female BALB/c mice were injected orthotopically in the mammary fat pad with 4T1 tumor cells. Treatment consisted of irradiated 4T1 ± BCG cells given subcutaneously every 4 days and was repeated three times per mouse when tumors became palpable. Tumors were measured two to three times per week for 25 days. The vaccine’s activity was confirmed in a second experiment using Lewis lung carcinoma (LLC) cells in C57BL/6 mice to exclude a model specific effect. Interferon-γ (IFN-γ) and interleukin-2 (IL-2) enzyme-linked immunospots (ELISPOTS) were performed on splenic lymphocytes incubated with 4T1 lysates along with immunohistochemistry for CD3 on tumor sections. Results Tumor growth was significantly inhibited in the 4T1-BCG and LLC-BCG treatment groups when compared to 4T1 and LLC treatment groups. There were higher levels of IL-2 and IFN-γ secreting T-cells on ELISPOT for BCG treated groups, and a trend for higher numbers of tumor infiltrating CD3+ lymphocytes. Some tumors in the 4T1-BCG demonstrated organized lymphoid structures within the tumor microenvironment as well. Conclusion The use of BCG bystander cell lines demonstrates proof of concept for anti-tumor activity and immunogenicity in an immunocompetent murine model of breast cancer. This vaccine is being evaluated in lung cancer and should be explored further in clinical trials of breast cancer patients at high risk of recurrence or in combination with other immunomodulatory agents.
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Affiliation(s)
- Hatem Soliman
- Department of Women's Oncology and Experimental Therapeutics, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Scott J Antonia
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Zhai Y, Zhou Y, Li X, Feng G. Immune-enhancing effect of nano-DNA vaccine encoding a gene of the prME protein of Japanese encephalitis virus and BALB/c mouse granulocyte-macrophage colony-stimulating factor. Mol Med Rep 2015; 12:199-209. [PMID: 25738258 PMCID: PMC4438877 DOI: 10.3892/mmr.2015.3419] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 01/02/2015] [Indexed: 11/12/2022] Open
Abstract
Plasmid-encoded granulocyte-macrophage colony-stimulating factor (GM-CSF) is an adjuvant for genetic vaccines; however, how GM-CSF enhances immunogenicity remains to be elucidated. In the present study, it was demonstrated that injection of a plasmid encoding the premembrane (prM) and envelope (E) protein of Japanese encephalitis virus and mouse GM-CSF (pJME/GM-CSF) into mouse muscle recruited large and multifocal conglomerates of macrophages and granulocytes, predominantly neutrophils. During the peak of the infiltration, an appreciable number of immature dendritic cells (DCs) appeared, although no T and B-cells was detected. pJME/GM-CSF increased the number of splenic DCs and the expression of major histocompatibility complex class II (MHCII) on splenic DC, and enhanced the antigenic capture, processing and presentation functions of splenic DCs, and the cell-mediated immunity induced by the vaccine. These findings suggested that the immune-enhancing effect by pJME/GM-CSF was associated with infiltrate size and the appearance of integrin αx (CD11c)+cells. Chitosan-pJME/GM-CSF nanoparticles, prepared by coacervation via intramuscular injection, outperformed standard pJME/GM-CSF administrations in DC recruitment, antigen processing and presentation, and vaccine enhancement. This revealed that muscular injection of chitosan-pJME/GM-CSF nanoparticles may enhance the immunoadjuvant properties of GM-CSF.
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Affiliation(s)
- Yongzhen Zhai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yan Zhou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ximei Li
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Guohe Feng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Caruana I, Weber G, Ballard BC, Wood MS, Savoldo B, Dotti G. K562-Derived Whole-Cell Vaccine Enhances Antitumor Responses of CAR-Redirected Virus-Specific Cytotoxic T Lymphocytes In Vivo. Clin Cancer Res 2015; 21:2952-62. [PMID: 25691731 DOI: 10.1158/1078-0432.ccr-14-2998] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 02/09/2015] [Indexed: 01/22/2023]
Abstract
PURPOSE Adoptive transfer of Epstein-Barr virus (EBV)-specific and cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) genetically modified to express a chimeric antigen receptor (CAR) induces objective tumor responses in clinical trials. In vivo expansion and persistence of these cells are crucial to achieve sustained clinical responses. We aimed to develop an off-the-shelf whole-cell vaccine to boost CAR-redirected virus-specific CTLs in vivo after adoptive transfer. As proof of principle, we validated our vaccine approach by boosting CMV-specific CTLs (CMV-CTLs) engineered with a CAR that targets the GD2 antigen. EXPERIMENTAL DESIGN We generated the whole-cell vaccine by engineering the K562 cell line to express the CMV-pp65 protein and the immune stimulatory molecules CD40L and OX40L. Single-cell-derived clones were used to stimulate CMV-CTLs in vitro and in vivo in a xenograft model. We also assessed whether the in vivo boosting of CAR-redirected CMV-CTLs with the whole-cell vaccine enhances the antitumor responses. Finally, we addressed potential safety concerns by including the inducible safety switch caspase9 (iC9) gene in the whole-cell vaccine. RESULTS We found that K562-expressing CMV-pp65, CD40L, and OX40L effectively stimulate CMV-specific responses in vitro by promoting antigen cross-presentation to professional antigen-presenting cells (APCs). Vaccination also enhances antitumor effects of CAR-redirected CMV-CTLs in xenograft tumor models. Activation of the iC9 gene successfully induces growth arrest of engineered K562 implanted in mice. CONCLUSIONS Vaccination with a whole-cell vaccine obtained from K562 engineered to express CMV-pp65, CD40L, OX40L and iC9 can safely enhance the antitumor effects of CAR-redirected CMV-CTLs.
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Affiliation(s)
- Ignazio Caruana
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas
| | - Gerrit Weber
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas
| | - Brandon C Ballard
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas
| | - Michael S Wood
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas
| | - Barbara Savoldo
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas. Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Gianpietro Dotti
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas. Department of Immunology, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.
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McDonnell AM, Lesterhuis WJ, Khong A, Nowak AK, Lake RA, Currie AJ, Robinson BWS. Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy. Eur J Immunol 2014; 45:49-59. [PMID: 25316312 DOI: 10.1002/eji.201444722] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 09/19/2014] [Accepted: 10/10/2014] [Indexed: 11/11/2022]
Abstract
Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8(+) T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b(+) DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take up, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.
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Affiliation(s)
- Alison M McDonnell
- National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, The University of Western Australia, Nedlands, WA, Australia
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Subbotin VM. Dendritic cell-based cancer immunotherapy: the stagnant approach and a theoretical solution. Drug Discov Today 2014; 19:834-7. [DOI: 10.1016/j.drudis.2014.02.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 02/06/2014] [Accepted: 02/25/2014] [Indexed: 01/06/2023]
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Nebiker CA, Han J, Eppenberger-Castori S, Iezzi G, Hirt C, Amicarella F, Cremonesi E, Huber X, Padovan E, Angrisani B, Droeser RA, Rosso R, Bolli M, Oertli D, von Holzen U, Adamina M, Muraro MG, Mengus C, Zajac P, Sconocchia G, Zuber M, Tornillo L, Terracciano L, Spagnoli GC. GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer. Clin Cancer Res 2014; 20:3094-106. [PMID: 24737547 DOI: 10.1158/1078-0432.ccr-13-2774] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Colorectal cancer infiltration by CD16(+) myeloid cells correlates with improved prognosis. We addressed mechanistic clues and gene and protein expression of cytokines potentially associated with macrophage polarization. EXPERIMENTAL DESIGN GM-CSF or M-CSF-stimulated peripheral blood CD14(+) cells from healthy donors were cocultured with colorectal cancer cells. Tumor cell proliferation was assessed by (3)H-thymidine incorporation. Expression of cytokine genes in colorectal cancer and autologous healthy mucosa was tested by quantitative, real-time PCR. A tumor microarray (TMA) including >1,200 colorectal cancer specimens was stained with GM-CSF- and M-CSF-specific antibodies. Clinicopathological features and overall survival were analyzed. RESULTS GM-CSF induced CD16 expression in 66% ± 8% of monocytes, as compared with 28% ± 1% in cells stimulated by M-CSF (P = 0.011). GM-CSF but not M-CSF-stimulated macrophages significantly (P < 0.02) inhibited colorectal cancer cell proliferation. GM-CSF gene was expressed to significantly (n = 45, P < 0.0001) higher extents in colorectal cancer than in healthy mucosa, whereas M-CSF gene expression was similar in healthy mucosa and colorectal cancer. Accordingly, IL1β and IL23 genes, typically expressed by M1 macrophages, were expressed to significantly (P < 0.001) higher extents in colorectal cancer than in healthy mucosa. TMA staining revealed that GM-CSF production by tumor cells is associated with lower T stage (P = 0.02), "pushing" growth pattern (P = 0.004) and significantly (P = 0.0002) longer survival in mismatch-repair proficient colorectal cancer. Favorable prognostic effect of GM-CSF production by colorectal cancer cells was confirmed by multivariate analysis and was independent from CD16(+) and CD8(+) cell colorectal cancer infiltration. M-CSF expression had no significant prognostic relevance. CONCLUSIONS GM-CSF production by tumor cells is an independent favorable prognostic factor in colorectal cancer.
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Affiliation(s)
- Christian A Nebiker
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Junyi Han
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Serenella Eppenberger-Castori
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Giandomenica Iezzi
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Christian Hirt
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Francesca Amicarella
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Eleonora Cremonesi
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Xaver Huber
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Elisabetta Padovan
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Basilio Angrisani
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Raoul A Droeser
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, ItalyAuthors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Raffaele Rosso
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Martin Bolli
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Daniel Oertli
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Urs von Holzen
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Michel Adamina
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Manuele G Muraro
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Chantal Mengus
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Paul Zajac
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Giuseppe Sconocchia
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Markus Zuber
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Luigi Tornillo
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Luigi Terracciano
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Giulio C Spagnoli
- Authors' Affiliations: Department of Biomedicine, Institute for Surgical Research; Institute of Pathology, University of Basel; Department of Surgery, University Hospital, Basel; Ospedale Regionale, Lugano; Ospedale Regionale "San Giovanni," Bellinzona; Department of Surgery, Kantonsspital, St Gallen; Department of Surgery, Kantonsspital, Olten, Switzerland; Departments of General Surgery and Gastroenterology, Shanghai East Hospital, Tongji University, Shanghai, P.R. China; and Institute of Translational Pharmacology, National Research Council, Rome, Italy
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Phase II trial of a GM-CSF-producing and CD40L-expressing bystander cell line combined with an allogeneic tumor cell-based vaccine for refractory lung adenocarcinoma. J Immunother 2014; 36:442-50. [PMID: 23994887 DOI: 10.1097/cji.0b013e3182a80237] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized that the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given q14 days×3, followed by monthly ×3. Cyclophosphamide (300 mg/m IV) was administered before the first and fourth vaccines to deplete regulatory T cells. All-trans retinoic acid was given (150/mg/m/d) after the first and fourth vaccines to enhance dendritic cell differentiation. Twenty-four participants were accrued at a single institution from October 2006 to June 2008, with a median age 64 years and median of 4 previous lines of systemic therapy. A total of 101 vaccines were administered. Common toxicities were headache (54%) and site reaction (38%). No radiologic responses were observed. Median overall survival was 7.9 months and median progression-free survival was 1.7 months. Of 14 patients evaluable for immunological study, 5 had peptide-induced CD8 T-cell activation after vaccination. Overall, vaccine administration was feasible in an extensively pretreated population of metastatic lung cancer. Despite a suggestion of clinical activity in the subset with immune response, the trial did not meet the primary endpoint of inducing radiologic tumor regression.
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Li D, Wang W, Shi HS, Fu YJ, Chen X, Chen XC, Liu YT, Kan B, Wang YS. Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects. Hum Gene Ther 2013; 25:63-72. [PMID: 24134464 DOI: 10.1089/hum.2013.161] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Beta-defensins, small antimicrobial peptides, are involved in host immune responses to tumors. In this study, we used beta-defensin 2 (BD2) to explore the possible role of beta-defensins in cancer gene therapy. A recombinant plasmid expressing a secretable form of BD2 was constructed. The biological activities of BD2 in immature dendritic cells (iDCs) were tested in vitro and in vivo. The antitumor effects were investigated in three established tumor models. The secreted BD2 was detected and exhibited chemotactic activity in iDCs both in vitro and in vivo. Recruitment and activation of iDCs in tumor niches resulted in significant tumor growth inhibition. Adoptive transfer of splenocytes and depletion of immune cell subsets revealed that CD8(+) T lymphocyte responses mediated the increased tumor inhibition. Furthermore, we also found that chemotactic and maturation-inducing activities in iDCs in tumor milieu contributed to enhanced local antitumor effects. Our study indicates that gene therapy with BD2 can mediate specific antitumor immunity and augment local antitumor effects. Our study also suggested that beta-defensins may merit further exploration for cancer immunotherapy as promising immunogenes.
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Affiliation(s)
- Dan Li
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu 610042, P.R. China
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18
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Mauri G, Chiodoni C, Parenza M, Arioli I, Tripodo C, Colombo MP. Ultrasound-guided intra-tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer. Cancer Immunol Immunother 2013; 62:1811-9. [PMID: 24136641 PMCID: PMC11028892 DOI: 10.1007/s00262-013-1486-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 10/05/2013] [Indexed: 10/26/2022]
Abstract
Intra-tumor injection of immunotherapeutic agents is often the most effective, likely because of concomitant modification of tumor microenvironment. We tested an immunotherapeutic regimen consisting of CpG oligonucleotides and of adenovirus-mediated gene delivery of CCL16 chemokine directly into orthotopically implanted prostate tumors by ultrasound-guided injection, followed by systemic administration of an anti-IL-10R antibody. This combination treatment induced rapid stromal rearrangement, characterized by massive leukocyte infiltration and large areas of necrosis, a scenario that eventually led to complete tumor rejection and systemic immunity in 75 % of the treated mice. In vivo T lymphocyte depletion experiments demonstrated that the efficacy of CCL16/CpG/anti-IL-10R combination treatment relies upon CD8 T lymphocytes whereas CD4 T cells are dispensable. The results underlie the feasibility of echo-guided local immunotherapy of tumors located in visceral organs that are not easily accessible.
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Affiliation(s)
- Giorgio Mauri
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Claudia Chiodoni
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Mariella Parenza
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Ivano Arioli
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy
| | - Claudio Tripodo
- Department of Human Pathology, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy
| | - Mario Paolo Colombo
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy
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19
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Quetglas JI, Rodriguez-Madoz JR, Bezunartea J, Ruiz-Guillen M, Casales E, Medina-Echeverz J, Prieto J, Berraondo P, Hervas-Stubbs S, Smerdou C. Eradication of liver-implanted tumors by Semliki Forest virus expressing IL-12 requires efficient long-term immune responses. THE JOURNAL OF IMMUNOLOGY 2013; 190:2994-3004. [PMID: 23401594 DOI: 10.4049/jimmunol.1201791] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Semliki Forest virus vectors expressing IL-12 (SFV-IL-12) were shown to induce potent antitumor responses against s.c. MC38 colon adenocarcinomas in immunocompetent mice. However, when MC38 tumors were implanted in liver, where colon tumors usually metastasize, SFV-IL-12 efficacy was significantly reduced. We reasoned that characterization of immune responses against intrahepatic tumors in responder and nonresponder animals could provide useful information for designing more potent antitumor strategies. Remarkably, SFV-IL-12 induced a high percentage of circulating tumor-specific CD8 T cells in all treated animals. Depletion studies showed that these cells were essential for SFV-IL-12 antitumor activity. However, in comparison with nonresponders, tumor-specific cells from responder mice acquired an effector-like phenotype significantly earlier, were recruited more efficiently to the liver, and, importantly, persisted for a longer period of time. All treated mice had high levels of functional specific CD8 T cells at 8 d posttreatment reflected by both in vivo killing and IFN-γ-production assays, but responder animals showed a more avid and persistent IFN-γ response. Interestingly, differences in immune responses between responders and nonresponders seemed to correlate with the immune status of the animals before treatment and were not due to the treatment itself. Mice that rejected tumors were protected against tumor rechallenge, indicating that sustained memory responses are required for an efficacious therapy. Interestingly, tumor-specific CD8 T cells of responder animals showed upregulation of IL-15Rα expression compared with nonresponders. These results suggest that SFV-IL-12 therapy could benefit from the use of strategies that could either upregulate IL-15Rα expression or activate this receptor.
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Affiliation(s)
- Jose I Quetglas
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Navarra, Spain
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20
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Rakhmilevich AL, Alderson KL, Sondel PM. T-cell-independent antitumor effects of CD40 ligation. Int Rev Immunol 2012; 31:267-78. [PMID: 22804571 DOI: 10.3109/08830185.2012.698337] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CD40 ligation has been shown to induce antitumor effects in mice and cancer patients. Most of the studies have focused on the ability of an agonistic anti-CD40 mAb to either directly kill CD40-positive tumor cells or activate T-cell immune responses. In this review the authors focus on the ability of CD40 ligation to activate antitumor effector mechanisms of the cells of innate immunity such as macrophages and NK cells.
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Affiliation(s)
- Alexander L Rakhmilevich
- Department of Human Oncology and Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
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21
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Öhman J, Magnusson B, Telemo E, Jontell M, Hasséus B. Langerhans cells and T cells sense cell dysplasia in oral leukoplakias and oral squamous cell carcinomas--evidence for immunosurveillance. Scand J Immunol 2012; 76:39-48. [PMID: 22469080 DOI: 10.1111/j.1365-3083.2012.02701.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Leukoplakias (LPLs) are lesions in the oral mucosa that may develop into oral squamous cell carcinoma (OSCC). The objective of this study was to assess presence and distribution of dendritic Langerhans cells (LCs) and T cells in patients with LPLs with or without cell dysplasia and in oral squamous cell carcinoma (OSCC). Biopsy specimens from patients with leukoplakias (LPLs) with or without dysplasia and oral squamous cell carcinoma (OSCC) were immunostained with antibodies against CD1a, Langerin, CD3, CD4, CD8 and Ki67, followed by quantitative analysis. Analyses of epithelium and connective tissue revealed a significantly higher number of CD1a + LCs in LPLs with dysplasia compared with LPLs without dysplasia. Presence of Langerin + LCs in epithelium did not differ significantly between LPLs either with or without dysplasia and OSCC. T cells were found in significantly increased numbers in LPLs with dysplasia and OSCC. The number of CD4+ cells did not differ significantly between LPLs with and without dysplasia, but a significant increase was detected when comparing LPLs with dysplasia with OSCC. CD8+ cells were significantly more abundant in OSCC and LPLs with dysplasia compared with LPLs without dysplasia. Proliferating cells (Ki67+) were significantly more abundant in OSCC compared to LPLs with dysplasia. Confocal laser scanning microscopy revealed colocalization of LCs and T cells in LPLs with dysplasia and in OSCC. LCs and T cells are more numerous in tissue compartments with dysplastic epithelial cells and dramatically increase in OSCC. This indicates an ongoing immune response against cells with dysplasia.
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Affiliation(s)
- J Öhman
- Department of Oral Medicine and Pathology, Institute of Odontology, Gothenburg, Sweden.
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22
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A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen. PLoS One 2012; 7:e44707. [PMID: 22970293 PMCID: PMC3435279 DOI: 10.1371/journal.pone.0044707] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 08/07/2012] [Indexed: 12/14/2022] Open
Abstract
NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8+ T cell epitope, NY-ESO-188–96 (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1157–165 epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-188–96 is much more efficiently cross-presented from the soluble form, than NY-ESO-1157–165. On the other hand, NY-ESO-1157–165 is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A26–35; whereas NY-ESO-188–96 was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-188–96 is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18+ melanoma patients. Surprisingly, all the detectable responses to NY-ESO-188–96 from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8+ T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed.
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23
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Burocchi A, Pittoni P, Gorzanelli A, Colombo MP, Piconese S. Intratumor OX40 stimulation inhibits IRF1 expression and IL-10 production by Treg cells while enhancing CD40L expression by effector memory T cells. Eur J Immunol 2012; 41:3615-26. [PMID: 22229156 DOI: 10.1002/eji.201141700] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4+ populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor.
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Affiliation(s)
- Alessia Burocchi
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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24
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Ataera H, Hyde E, Price KM, Stoitzner P, Ronchese F. Murine melanoma-infiltrating dendritic cells are defective in antigen presenting function regardless of the presence of CD4CD25 regulatory T cells. PLoS One 2011; 6:e17515. [PMID: 21390236 PMCID: PMC3048402 DOI: 10.1371/journal.pone.0017515] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Accepted: 02/04/2011] [Indexed: 01/08/2023] Open
Abstract
Tumor-infiltrating dendritic cells are often ineffective at presenting tumor-derived antigen in vivo, a defect usually ascribed to the suppressive tumor environment. We investigated the effects of depleting CD4+CD25+ “natural” regulatory T cells (Treg) on the frequency, phenotype and function of total dendritic cell populations in B16.OVA tumors and in tumor-draining lymph nodes. Intraperitoneal injection of the anti-CD25 monoclonal antibody PC61 reduced Treg frequency in blood and tumors, but did not affect the frequency of tumor-infiltrating dendritic cells, or their expression of CD40, CD86 and MHCII. Tumor-infiltrating dendritic cells from PC61-treated or untreated mice induced the proliferation of allogeneic T cells in vitro, but could not induce proliferation of OVA-specific OTI and OTII T cells unless specific peptide antigen was added in culture. Some proliferation of naïve, OVA-specific OTI T cells, but not OTII T cells, was observed in the tumor-draining LN of mice carrying B16.OVA tumors, however, this was not improved by PC61 treatment. Experiments using RAG1−/− hosts adoptively transferred with OTI and CD25-depleted OTII cells also failed to show improved OTI and OTII T cell proliferation in vivo compared to C57BL/6 hosts. We conclude that the defective presentation of B16.OVA tumor antigen by tumor-infiltrating dendritic cells and in the tumor-draining lymph node is not due to the presence of “natural” CD4+CD25+ Treg.
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Affiliation(s)
- Haley Ataera
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Evelyn Hyde
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Kylie M. Price
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | | | - Franca Ronchese
- Malaghan Institute of Medical Research, Wellington, New Zealand
- * E-mail:
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25
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Targeted cancer therapy: dendritic cell metabolism. Ther Deliv 2011; 2:133-6. [PMID: 22833938 DOI: 10.4155/tde.10.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Dubrot J, Palazón A, Alfaro C, Azpilikueta A, Ochoa MC, Rouzaut A, Martinez-Forero I, Teijeira A, Berraondo P, Le Bon A, Hervás-Stubbs S, Melero I. Intratumoral injection of interferon-α and systemic delivery of agonist anti-CD137 monoclonal antibodies synergize for immunotherapy. Int J Cancer 2010; 128:105-18. [PMID: 20309938 DOI: 10.1002/ijc.25333] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
CD137 artificial costimulation results in complete tumor rejection in several mouse models. Type I interferons (IFN) exert antitumor effects through an array of molecular functions on malignant cells, tumor stroma and immune system cells. The fact that agonist anti-CD137 mAb induce tumor regressions in mice deficient in the unique receptor for Type I IFNs (IFNAR(-/-) ) indicated potential for treatment combinations. Indeed, combination of intratumor injections of mouse IFN-α and intraperitoneal injections of anti-CD137 mAb synergized as seen on subcutaneous lesions derived from the MC38 colon carcinoma, which is resistant to each treatment if given separately. Therapeutic activity was achieved both against lesions directly injected with IFN-α and against distant concomitant tumors. Experiments in bone marrow chimeras prepared with IFNAR(-/-) and WT mice concluded that expression of the receptor for Type I interferons is mainly required on cells of the hematopoietic compartment. Synergistic effects correlated with a remarkable cellular hyperplasia of the tumor draining lymph nodes (TDLNs). Enlarged TDLNs contained more plasmacytoid and conventional dendritic cells (DC) that more readily cross-presented. Importantly, numbers of both DC subtypes inversely correlated with the tumor size. Numbers of CD8 T cells specific for a dominant tumor antigen were increased at TDLNs by each separate treatment but only with slight augments due to the combination. Combined antitumor effects of the therapeutic strategy were also seen on subcutaneous TC-1 tumors established for 24 days before treatment onset. The described strategy is realistic because (i) agents of each kind are clinically available and (ii) equivalent procedures in humans are feasible.
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Affiliation(s)
- Juan Dubrot
- CIMA and Clinica Universitaria, Universidad de Navarra, Pamplona, Spain
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27
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Augier S, Ciucci T, Luci C, Carle GF, Blin-Wakkach C, Wakkach A. Inflammatory Blood Monocytes Contribute to Tumor Development and Represent a Privileged Target To Improve Host Immunosurveillance. THE JOURNAL OF IMMUNOLOGY 2010; 185:7165-73. [DOI: 10.4049/jimmunol.0902583] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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28
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Choi Y, Kim CW. Antitumor effects of combined granulocyte macrophage colony stimulating factor and macrophage inflammatory protein-3 alpha plasmid DNA. Cancer Sci 2010; 101:2341-50. [PMID: 20804501 PMCID: PMC11158867 DOI: 10.1111/j.1349-7006.2010.01704.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Dendritic cells (DC) are critical for priming adaptive immune responses to foreign antigens. However, the feasibility of harnessing these cells in vivo to optimize the antitumor effects has not been fully explored. The authors investigated a novel therapeutic approach that involves delivering synergistic signals that both recruit and expand DC populations at sites of intratumoral injection. More specifically, the authors examined whether the co-administration of plasmids encoding the chemokine macrophage inflammatory protein-3 alpha (pMIP3α) and plasmid encoding the granulocyte macrophage colony stimulating factor (pGM-CSF; a DC-specific growth factor) can recruit, expand and activate large numbers of DC at sites of intratumoral injection. It was found that the administration of pGM-CSF and pMIP3α resulted in dramatic recruitment and expansion of DC at these sites and in draining lymph nodes. Furthermore, treatment with pGM-CSF and pMIP3α generated the strongest MUC1-associated CD8+ T-cell immune responses in draining lymph nodes and in tumors, produced the greatest antitumor effects and enhanced survival rates more than pcDNA3.1, pGM-CSF alone and pMIP3α alone. It was also found that pGM-CSF plus pMIP3α generated the strongest MUC1-associated CD4+ T-cell immune responses in draining lymph nodes and in tumors. The findings of the present study suggest that the recruitment and activation of DC in vivo due to the synergistic actions of pGM-CSF and pMIP3α presents a potentially feasible means of controlling immunogenic malignancies and provides a basis for the development of novel immunotherapeutic treatments.
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Affiliation(s)
- Yun Choi
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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29
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Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery. Blood 2010; 116:218-25. [PMID: 20430956 DOI: 10.1182/blood-2009-10-249458] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)-A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c(+) blood DCs cross-presented NY-ESO-1-specific HLA-A2(157-165)-, HLA-B7(60-72)-, and HLA-Cw3(92-100)-restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1(157-165)/HLA-A2, NY-ESO-1(60-72)/HLA-B7, and NY-ESO-1(92-100)/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-1(60-72)/HLA-B7-restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A-, B-, and C-restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.
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30
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Wang YS, Li D, Shi HS, Wen YJ, Yang L, Xu N, Chen XC, Chen X, Chen P, Li J, Deng HX, Wang CT, Xie G, Huang S, Mao YQ, Chen LJ, Zhao X, Wei YQ. Intratumoral expression of mature human neutrophil peptide-1 mediates antitumor immunity in mice. Clin Cancer Res 2009; 15:6901-11. [PMID: 19861439 DOI: 10.1158/1078-0432.ccr-09-0484] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Human neutrophil peptides (HNP1-3), small molecular antimicrobial peptides, are expressed within tumors and associated with tumor necrosis and inhibition of angiogenesis. Recent investigations have suggested that HNP1-3 are likely to be involved in the host immune responses to tumors. EXPERIMENTAL DESIGN We used recombinant pSec-HNP1, which expresses a secretable form of HNP1, to obtain expression of HNP1 in the tumor milieu in immunocompetent mice to explore the possible roles of HNP1 in tumor immunity. The antitumor effects were investigated in established CT26 colon cancer and 4T1 breast cancer models. RESULTS HNP1-mediated chemotactic and activating effects on immature dendritic cells were detected both in vitro and in vivo. Intratumoral expression of HNP1 resulted in not only significant tumor growth inhibition but also increased CTL infiltration within tumors. Adoptive transfer of splenocytes and a (51)Cr release assay revealed specific cellular immune responses. Furthermore, increased antibodies were also found in sera from pSec-HNP1-treated mice supporting specific humoral immune responses. Increased apoptosis and decreased angiogenesis were also shown in treated tumors. CONCLUSIONS These findings indicate that HNP1 can exert multiple antitumor effects through different mechanisms; more importantly, HNP1 mediates host immune responses to tumors in situ through the recruitment and subsequent activation of immature dendritic cells and thus shows promising potential in cancer therapy.
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Affiliation(s)
- Yong-Sheng Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Department of Gynecology and Obstetrics, Second West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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31
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Selective expression of human immunodeficiency virus Nef in specific immune cell populations of transgenic mice is associated with distinct AIDS-like phenotypes. J Virol 2009; 83:9743-58. [PMID: 19605470 DOI: 10.1128/jvi.00125-09] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We previously reported that CD4C/human immunodeficiency virus (HIV)(Nef) transgenic (Tg) mice, expressing Nef in CD4(+) T cells and cells of the macrophage/dendritic cell (DC) lineage, develop a severe AIDS-like disease, characterized by depletion of CD4(+) T cells, as well as lung, heart, and kidney diseases. In order to determine the contribution of distinct populations of hematopoietic cells to the development of this AIDS-like disease, five additional Tg strains expressing Nef through restricted cell-specific regulatory elements were generated. These Tg strains express Nef in CD4(+) T cells, DCs, and macrophages (CD4E/HIV(Nef)); in CD4(+) T cells and DCs (mCD4/HIV(Nef) and CD4F/HIV(Nef)); in macrophages and DCs (CD68/HIV(Nef)); or mainly in DCs (CD11c/HIV(Nef)). None of these Tg strains developed significant lung and kidney diseases, suggesting the existence of as-yet-unidentified Nef-expressing cell subset(s) that are responsible for inducing organ disease in CD4C/HIV(Nef) Tg mice. Mice from all five strains developed persistent oral carriage of Candida albicans, suggesting an impaired immune function. Only strains expressing Nef in CD4(+) T cells showed CD4(+) T-cell depletion, activation, and apoptosis. These results demonstrate that expression of Nef in CD4(+) T cells is the primary determinant of their depletion. Therefore, the pattern of Nef expression in specific cell population(s) largely determines the nature of the resulting pathological changes.
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Pinilla-Ibarz J, Shah B, Dubovsky JA. The biological basis for immunotherapy in patients with chronic myelogenous leukemia. Cancer Control 2009; 16:141-52. [PMID: 19337200 DOI: 10.1177/107327480901600206] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Chronic myelogenous leukemia (CML) has long been recognized as an entity responsive to immunotherapeutic interventions. Despite the success of the tyrosine kinase inhibitors (TKIs) in this disease, CML remains incurable. Only allogeneic bone marrow transplantation can provide long-term eradication of CML. METHODS This review summarizes the recent advances in the field of immunology in CML, specifically in tumor antigen discovery, that have been incorporated into the design of new clinical trials. RESULTS Multiple vaccine approaches are currently under clinical investigation. Recent laboratory and clinical data also point to a unique interaction of TKIs with the immune system. CONCLUSIONS A better understanding of these interactions combined with advances in the field of immunotherapy will likely lead to incorporation of TKIs in future therapeutic interventions to develop a cure for this disease.
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Affiliation(s)
- Javier Pinilla-Ibarz
- Department of Malignant Hematology at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA.
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33
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Targeting the intratumoral dendritic cells by the oncolytic adenoviral vaccine expressing RANTES elicits potent antitumor immunity. J Immunother 2009; 32:145-56. [PMID: 19238013 DOI: 10.1097/cji.0b013e318193d31e] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Dendritic cells (DCs) are professional antigen (Ag)-presenting cells capable of inducing immune responses to tumor Ags and, therefore, play a central role in the induction of antitumor immunity. There is a large amount of evidence, however, about paucity of tumor-associated DCs and that DCs' immunogenic functions are suppressed in a tumor environment. Here we describe a potent in situ vaccine targeting tumoral DCs in vivo. This vaccine comprised of an oncolytic adenovirus expressing RANTES (regulated upon activation, normally T expressed, and presumably secreted) (Ad-RANTES-E1A), enhanced tumor infiltration, and maturation of Ag-presenting cells in vivo. In this study, we show that intratumoral vaccinations with Ad-RANTES-E1A induced significant primary tumor growth regression and blocked metastasis formation in JC and E.G-7 murine tumor models. This vaccine recruited DCs, macrophages, natural killer cells, and CD8+ T cells to the tumor site, and thus enhanced Ag-specific cytotoxic T lymphocyte responses and natural killer cell responses. DCs purified from the Ad-RANTES-E1A-treated E.G-7 tumors secreted significantly higher levels of interferon-gamma and interleukin-12, as compared with control groups and more efficiently enhanced CD8+ T-cell response. This in situ immunization strategy could be a potent antitumor immunotherapy approach for aggressive established tumors.
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Stoitzner P, Green LK, Jung JY, Price KM, Atarea H, Kivell B, Ronchese F. Inefficient presentation of tumor-derived antigen by tumor-infiltrating dendritic cells. Cancer Immunol Immunother 2008; 57:1665-73. [PMID: 18311487 PMCID: PMC11029823 DOI: 10.1007/s00262-008-0487-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2007] [Accepted: 02/12/2008] [Indexed: 11/30/2022]
Abstract
BACKGROUND Transplantable B16 melanoma is widely used as a tumor model to investigate tumor immunity. We wished to characterize the leukocyte populations infiltrating B16 melanoma tumors, and the functional properties of tumor-infiltrating dendritic cells (TIDC). MATERIALS AND METHODS We used the B16 melanoma cell line expressing ovalbumin protein (OVA) to investigate the phenotype and T cell stimulatory capacity of TIDC. RESULTS The majority of leukocytes in B16 melanoma were macrophages, which colocalized with TIDCs, B and T cells to the peripheral area of the tumor. Both myeloid and plasmacytoid DC populations were present within tumors. Most of these DCs appeared immature, but about a third expressed a mature phenotype. TIDCs did not present tumor-derived antigen, as they were unable to induce the proliferation of tumor-specific CD4+ and CD8+ T cells in vitro unless in the presence of specific peptides. Some presentation of tumor-derived antigen could be demonstrated in the tumor-draining lymph node using in vivo proliferation assays. However, while proliferation of CD8+ T cells was reproducibly demonstrated, no proliferation of CD4+ T cells was observed. CONCLUSION In summary, our data suggest that DCs in tumors have limited antigen-presenting function. Inefficient antigen presentation extends to the tumor-draining lymph node, and may affect the generation of antitumor immune responses.
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Iida T, Shiba H, Misawa T, Ohashi T, Eto Y, Yanaga K. Adenovirus-mediated CD40L gene therapy induced both humoral and cellular immunity against rat model of hepatocellular carcinoma. Cancer Sci 2008; 99:2097-103. [PMID: 19016771 PMCID: PMC11159781 DOI: 10.1111/j.1349-7006.2008.00953.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2008] [Revised: 07/06/2008] [Accepted: 06/27/2008] [Indexed: 11/29/2022] Open
Abstract
Adenoviral-vector expressing CD40L (AxCAmCD40L)-mediated gene therapy was studied for treatment of hepatocellular carcinoma (HCC) using CD40 ligand (CD40L) complementary DNA in rats. The particular focus was whether humoral immunity took part in antitumor effect. When tumor cells transduced by AxCAmCD40L were implanted into the subcutaneous tissues of syngeneic rats, the tumor growth was suppressed. Intratumoral injection of AxCAmCD40L to pre-existing tumor in rats also led to significant reduction of tumor size. When tumor cells were re-implanted to prevention model rats and treatment model rats, no tumor growth was observed. Many studies to date have reported that cellular immunity induces antitumor immunity. However, the present study demonstrated that not only cellular immunity but also humoral immunity plays an essential role in a HCC model. These observations suggested that CD40L-mediated immune gene therapy for HCC was very effective treatment by activation of both cellular and humoral immune system.
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MESH Headings
- Adenoviridae/genetics
- Animals
- Antibody Formation
- CD40 Ligand/genetics
- CD40 Ligand/immunology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Disease Models, Animal
- Gene Transfer Techniques
- Genetic Therapy/methods
- Genetic Vectors
- Immunity, Cellular
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/immunology
- Liver Neoplasms, Experimental/prevention & control
- Rats
- Rats, Inbred BUF
- Survival Analysis
- Tumor Burden
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Tomonori Iida
- Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
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Arcuri M, Cappelletti M, Zampaglione I, Aurisicchio L, Nicosia A, Ciliberto G, Fattori E. Synergistic effect of gene-electro transfer and adjuvant cytokines in increasing the potency of hepatitis C virus genetic vaccination. J Gene Med 2008; 10:1048-54. [DOI: 10.1002/jgm.1217] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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37
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Iida T, Shiba H, Misawa T, Ohashi T, Eto Y, Yanaga K. Adenovirus-mediated CD40L gene therapy induced both humoral and cellular immunity against rat model of hepatocellular carcinoma. Cancer Sci 2008. [DOI: 10.1111/j.1349-7006.2007.00953.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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38
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Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF. Characterization of IL-10-Secreting T Cells Derived from Regulatory CD4+CD25+ Cells by the TIRC7 Surface Marker. THE JOURNAL OF IMMUNOLOGY 2008; 180:6054-63. [DOI: 10.4049/jimmunol.180.9.6054] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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39
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Degl'Innocenti E, Grioni M, Capuano G, Jachetti E, Freschi M, Bertilaccio MT, Hess-Michelini R, Doglioni C, Bellone M. Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells. Cancer Res 2008; 68:292-300. [DOI: 10.1158/0008-5472.can-07-2429] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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40
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Cayeux S, Bukarica B, Buschow C, Charo J, Bunse M, Dörken B, Blankenstein T. In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine. Gene Ther 2007; 14:1481-91. [PMID: 17700709 DOI: 10.1038/sj.gt.3303003] [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: 11/09/2022]
Abstract
One of the factors influencing the efficacy of tumour cell vaccines is the site of immunization. We have shown previously that gene-modified vaccines delivered directly inside the spleen induced antigen cross-presentation by splenic antigen-presenting cells (not B cells). Here, we examined the interaction between splenic CD11c(+) cells and antigen-specific CD4(+) T cells. We used tumour cells expressing ovalbumin (OVA), a situation where CD4(+) T-cell help is required for the generation of a cytotoxic T lymphocyte response. Using in vivo bioluminescence imaging of luciferase-expressing EL4-OVA cells, we could demonstrate that tumour cells were located exclusively inside the spleen following intrasplenic injection. We showed that after intrasplenic immunization with T/SA-OVA cells, splenic class I(+) class II(+) CD11c(+) cells engulfed and presented in vivo the OVA class I-restricted peptide SIINFEKL. However, in vivo previously adoptively transferred 5,6-carboxy-succinimidyl-fluorescein-ester-labelled transgenic CD4(+)KJI-26(+) cells specific for the class II OVA(323-339) peptide underwent abortive proliferation in the spleen. These CD4(+)KJI-26(+) cells were only transiently activated and produced IL-10 and IL-4 and not IFN-gamma. It appears that splenic CD11c(+) cells can downregulate splenic specific CD4(+) T-cell response thereby leading to a decrease in antitumour systemic immunity.
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Affiliation(s)
- S Cayeux
- Charité-am-MDC, Campus Buch, Berlin, Germany.
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41
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Preynat-Seauve O, Contassot E, Schuler P, French LE, Huard B. Melanoma-infiltrating dendritic cells induce protective antitumor responses mediated by T cells. Melanoma Res 2007; 17:169-76. [PMID: 17505262 DOI: 10.1097/cmr.0b013e3281844531] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Dendritic cells are the most potent antigen-presenting cells inducing innate and adaptive immune response. Dendritic cells infiltrate melanomas, but their ability to induce host antitumor immunity remains obscure. In a previous study, we have observed that melanoma-infiltrating dendritic cells have the capacity to process antigens and migrate to lymph nodes to prime T lymphocytes. Here, we observed that melanoma-infiltrating dendritic cells extracted from melanoma without any additional manipulations were able to protect naive mice against a lethal challenge with the tumor. Remarkably, this was achieved with reinjection of 10(5) melanoma-infiltrating dendritic cells, a number that did not exceed the total number of melanoma-infiltrating dendritic cells recovered from one single tumor. Three observations indicate that protection was due to the natural loading of melanoma-infiltrating dendritic cells with tumor antigens. First, the protective effect was not observed with equivalent numbers of bone marrow-derived dendritic cells. Second, the protection induced was specific for the tumor from which the tumor-infiltrating dendritic cells were isolated. Third, depletion experiments indicate that both CD4+ and CD8+ T lymphocytes were required during the effector phase of the antitumor response. Hence, designing strategies aimed at rendering melanoma-infiltrating dendritic cells visible to host T cells may boost spontaneous antitumor immunity.
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MESH Headings
- Adoptive Transfer
- Animals
- Antigens, Neoplasm/immunology
- Bone Marrow Transplantation
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/immunology
- Cell Line, Tumor
- Dendritic Cells/immunology
- Dendritic Cells/transplantation
- Lymphocyte Activation
- Melanoma, Experimental/immunology
- Melanoma, Experimental/pathology
- Melanoma, Experimental/surgery
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Transgenic
- Ovalbumin/immunology
- Peptide Fragments/immunology
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Time Factors
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Affiliation(s)
- Olivier Preynat-Seauve
- Louis Jeantet Skin Cancer Laboratory, Department of Dermatology, Geneva University Hospital, Geneva, Switzerland.
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Li H, Dutuor A, Tao L, Fu X, Zhang X. Virotherapy with a type 2 herpes simplex virus-derived oncolytic virus induces potent antitumor immunity against neuroblastoma. Clin Cancer Res 2007; 13:316-22. [PMID: 17200370 DOI: 10.1158/1078-0432.ccr-06-1625] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE We recently constructed an oncolytic virus from type 2 herpes simplex virus (HSV-2) that selectively targets and kills tumor cells with an activated Ras signaling pathway. Designated FusOn-H2, this virus has shown several discrete killing mechanisms. Here, we evaluated the antitumor immune responses after FusOn-H2-mediated virotherapy in a syngeneic murine neuroblastoma model. EXPERIMENTAL DESIGN We directly injected FusOn-H2 into established tumors and then measured its antitumor effect and the accompanying tumor-specific immune responses. Several oncolytic HSVs constructed from HSV-1 were included in the same experiments for comparisons. RESULTS Our data show that tumor destruction by FusOn-H2 in vivo induces potent antitumor immune responses in this syngeneic neuroblastoma model. The elicited cellular immunity not only eradicated neuroblastoma cells in vitro but also inhibited the growth of tumors at sites distant from the virus injection site. Moreover, adoptive transfer of splenocytes from mice receiving virotherapy to naïve mice resulted in a measurable antitumor effect. CONCLUSION We conclude that the ability of FusOn-H2 to induce tumor-specific cellular immunity expands the oncolytic repertoire of this virus and increases the likelihood that its use in patients would produce significant therapeutic benefits.
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Affiliation(s)
- Hongtao Li
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
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Murugaiyan G, Agrawal R, Mishra GC, Mitra D, Saha B. Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses. THE JOURNAL OF IMMUNOLOGY 2007; 178:2047-55. [PMID: 17277108 DOI: 10.4049/jimmunol.178.4.2047] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Establishment of host-protective memory T cells against tumors is the objective of an antitumor immunoprophylactic strategy such as reinforcing T cell costimulation via CD40-CD40L interaction. Previous CD40-targeted strategies assumed that T cell costimulation is an all-or-none phenomenon. It was unknown whether different levels of CD40L expression induce quantitatively and qualitatively different effector T cell responses. Using mice expressing different levels of CD40L, we demonstrated that the greater the T cell CD40L expression the less tumor growth occurred; the antitumor T cell response was host-protective. Lower levels of CD40L expression on T cells induced IL-10-mediated suppression of tumor-regressing effector CD8(+) T cells and higher productions of IL-4 and IL-10. Using mice expressing different levels of CD40 or by administering different doses of anti-CD40 Ab, similar observations were recorded implying that the induction of protumor or antitumor T cell responses was a function of the extent of CD40 cross-linking. IL-10 neutralization during priming with tumor Ags resulted in a stronger tumor-regressing effector T cell response. Using IL-10(-/-) DC for priming of mice expressing different levels of CD40L and subsequent transfer of the T cells from the primed mice to nu/nu mice, we demonstrated the protumor role of IL-10 in the induction of tumor-promoting T cells. Our results demonstrate that a dose-dependent cross-linking of a costimulatory molecule dictates the functional phenotype of the elicited effector T cell response. The T cell costimulation is a continuum of a function that induces not only graded T cell responses but also two counteracting responses at two extremes.
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Abstract
Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infiltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infiltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.
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45
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Dessureault S, Noyes D, Lee D, Dunn M, Janssen W, Cantor A, Sotomayor E, Messina J, Antonia SJ. A phase-I trial using a universal GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) in the formulation of autologous tumor cell-based vaccines for cancer patients with stage IV disease. Ann Surg Oncol 2006; 14:869-84. [PMID: 17103257 DOI: 10.1245/s10434-006-9196-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Revised: 07/10/2006] [Accepted: 07/13/2006] [Indexed: 11/18/2022]
Abstract
BACKGROUND Significant antitumor T-cell responses are generated in vitro when human lymphocytes are stimulated with autologous tumor cells in the presence of bystander cells transfected with CD40L and GM-CSF. Our goal was to test this bystander-based vaccine strategy in vivo in cancer patients with stage IV disease. METHODS Patients received three intradermal vaccine injections (irradiated autologous tumor cells plus GM.CD40L bystander cells) at 28-day intervals. Patients with no disease progression received three additional vaccines at 4, 12, and 24 months. Patients were monitored for toxicity, tumor response, and tumor-specific immune responses. RESULTS Twenty-one patients received at least three vaccine injections, with no toxicity attributable to the vaccine. Immunohistochemistry of vaccine injection site biopsies with CD1a and CD86 antibodies confirmed recruitment and activation of dendritic cells. There was no tumor regression after vaccination, but many patients had stable disease, including six of ten melanoma patients. Four patients developed tumor-specific T-cell responses on ELISPOT testing. One patient, who had stable disease for 24 months, demonstrated an increase in MART-1-specific T-cells by tetramer analysis after re-immunization; biopsy of the tumor that progressed 2 years after the onset of vaccination revealed a massive peritumoral and intratumoral T-cell infiltrate. CONCLUSIONS Vaccination of cancer patients with autologous tumor cells and GM.CD40L bystander cells (engineered to express GM-CSF and CD40L) is safe, can recruit and activate dendritic cells, and can elicit tumor-specific T-cell responses. Phase-II trials are underway to evaluate the impact of bystander-based vaccines on melanoma and mantle cell lymphoma.
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Affiliation(s)
- Sophie Dessureault
- Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, at the University of South Florida, Tampa, FL 33612, USA.
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Murugaiyan G, Agrawal R, Mishra GC, Mitra D, Saha B. Functional Dichotomy in CD40 Reciprocally Regulates Effector T Cell Functions. THE JOURNAL OF IMMUNOLOGY 2006; 177:6642-9. [PMID: 17082576 DOI: 10.4049/jimmunol.177.10.6642] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Activation of T cells requires signals through Ag-specific TCR and costimulatory molecules such as CD40L. Although the use of defined tumor Ags for the induction of protective T cells met with limited success, the CD40-CD40L interaction that was proposed to induce antitumor T cells did not prevent tumor growth completely. Using a model for prostate tumor, a leading cause of tumor-induced mortality in men, we show that the failure is due to a novel functional dichotomy of CD40 whereby it self-limits its antitumor functions by inducing IL-10. IL-10 prevents the CD40-induced CTL and TNF-alpha and IL-12 production, Th1 skewing, and tumor regression. Priming mice with tumor lysate-pulsed IL-10-deficient dendritic cells (DCs) or wild-type DC plus anti-IL-10 Ab establishes antitumor memory T cells that can transfer the protection into syngenic nude mice. Infusion of Ag-pulsed IL-10-deficient but not wild-type DCs back into syngenic mice results in successful therapeutic autovaccination. Thus, we demonstrate the IL-10-sensitive antitumor T cell memory formulating a novel prophylactic and therapeutic principle.
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MESH Headings
- Animals
- CD40 Antigens/immunology
- CD40 Antigens/metabolism
- CD40 Antigens/physiology
- Cell Line, Tumor
- Cells, Cultured
- Coculture Techniques
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Dendritic Cells/transplantation
- Dose-Response Relationship, Immunologic
- Immunologic Memory/genetics
- Immunotherapy, Adoptive
- Interleukin-10/biosynthesis
- Interleukin-10/deficiency
- Interleukin-10/genetics
- Interleukin-10/physiology
- Interleukin-12/antagonists & inhibitors
- Interleukin-12/biosynthesis
- Ligands
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Nude
- Neoplasm Transplantation
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/prevention & control
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/biosynthesis
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Kocak E, Lute K, Chang X, May KF, Exten KR, Zhang H, Abdessalam SF, Lehman AM, Jarjoura D, Zheng P, Liu Y. Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res 2006; 66:7276-84. [PMID: 16849577 DOI: 10.1158/0008-5472.can-05-2128] [Citation(s) in RCA: 138] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity.
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MESH Headings
- Animals
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- Antigens, CD/immunology
- Antigens, Differentiation/immunology
- Antineoplastic Combined Chemotherapy Protocols/immunology
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Autoimmunity/immunology
- CD8-Positive T-Lymphocytes/immunology
- CTLA-4 Antigen
- Colonic Neoplasms/immunology
- Colonic Neoplasms/therapy
- Female
- Humans
- Immunization, Passive/methods
- Mice
- Mice, Inbred C57BL
- Receptors, Nerve Growth Factor/immunology
- Receptors, Tumor Necrosis Factor/immunology
- T-Lymphocytes, Regulatory/immunology
- Tumor Necrosis Factor Receptor Superfamily, Member 9
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Affiliation(s)
- Ergun Kocak
- Division of Cancer Immunology, Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio, USA
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Du YC, Lin P, Zhang J, Lu YR, Ning QZ, Wang Q. Fusion of CpG-ODN-stimulating dendritic cells with Lewis lung cancer cells can enhance anti-tumor immune responses. ACTA ACUST UNITED AC 2006; 67:368-76. [PMID: 16671943 DOI: 10.1111/j.1399-0039.2006.00590.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Immunogenicity of tumor cells is generally weak. Therefore, dendritic cells (DCs) have been used to boost anti-tumor responses of DC-based vaccines. DC function is highly dependent on its subsets and the level of its maturation. Nowadays, DC/tumor cell fusion vaccines are already used in clinical trials, and there are numerous studies discussing the effects of cytidine-phosphate-guanosine-containing oligonucleotides (CpG-ODN) on various cell types including DC. CpG-ODN a powerful immuno-stimulant can drive DCs fully mature, thus improve the efficacy of vaccine therapy. There are two simple ways to help load tumor antigens onto DCs by direct contact with cells themselves: fusion or co-culture of DCs with whole tumor cells. In this study, we combined these two approaches to improve the efficacy of DC/tumor cell-based vaccine. Mature DCs are adept at presenting processed Ag to T cells with loss of its capacity to capture Ag, while immature DCs are on the contrary. Our results emphasize the necessity of considering the stage of DC maturation and corresponding choice of tumor antigen delivery when designing approaches for prophylaxis or therapy of tumors using DC-based immunization protocols. We used CpG-ODN-1826-stimulated mature DCs and non-CpG-ODN-stimulating DCs as sources of tumor antigen carriers to investigate the appropriate Ag-loading ways between fusion and co-culture. Our results displayed that DC/tumor vaccine using CpG-ODN-stimulating mature DCs fused, not co-cultured, with tumor cells can generate a consistent and highly effective anti-tumor immune responses in vivo.
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Affiliation(s)
- Y-C Du
- Division of Experimental Oncology, National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
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49
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Berhanu A, Huang J, Alber SM, Watkins SC, Storkus WJ. Combinational FLt3 ligand and granulocyte macrophage colony-stimulating factor treatment promotes enhanced tumor infiltration by dendritic cells and antitumor CD8(+) T-cell cross-priming but is ineffective as a therapy. Cancer Res 2006; 66:4895-903. [PMID: 16651446 DOI: 10.1158/0008-5472.can-05-2384] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Dendritic cells play significant roles in the development and maintenance of antitumor immune responses. Therapeutic recruitment of dendritic cells into the tumor microenvironment has the potential to result in enhanced antitumor T-cell cross-priming against a broad array of naturally processed and presented tumor-associated antigens. We have observed that the treatment of BALB/c mice bearing syngeneic CMS4 sarcomas with the combination of recombinant Flt3 ligand and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for five sequential days is sufficient to optimize the number of tumor-infiltrating dendritic cells (TIDC). However, despite the significant increase in the number of TIDCs, the therapeutic benefit of Flt3 ligand and GM-CSF treatment is minimal. Therapy-associated TIDCs do not exhibit a "suppressed" or "suppressor" phenotype in vitro, and their enhanced numbers in cytokine-treated mice were associated with increased levels of peripheral antitumor CD8(+) T effector cells and with an augmented population of CD8(+) tumor-infiltrating lymphocytes (TIL). These data suggest that Flt3 ligand + GM-CSF therapy of murine tumors fails at a mechanistic point that is downstream of specific T-cell priming by therapy-induced TIDCs and the recruitment of these T cells into the tumor microenvironment. Based on the enhanced infiltration of tumors by CD4(+)CD25(+) TIL in Flt3 ligand + GM-CSF-treated mice, this could reflect the dominant influence of regulatory T cells in situ.
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Affiliation(s)
- Aklile Berhanu
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
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Dzojic H, Loskog A, Tötterman TH, Essand M. Adenovirus-mediated CD40 ligand therapy induces tumor cell apoptosis and systemic immunity in the TRAMP-C2 mouse prostate cancer model. Prostate 2006; 66:831-8. [PMID: 16491482 DOI: 10.1002/pros.20344] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The interaction between CD40 ligand (CD40L) and CD40 on antigen presenting cells is essential for the initiation of antigen-specific T-cell responses, whereas CD40L stimulation of CD40+ tumor cells can induce cellular apoptosis. We investigated the anti-tumor effects induced by CD40L gene transfer into the mouse prostate adenocarcinoma cell line TRAMP-C2, both in vitro and in vivo. METHODS TRAMP-C2 cells were transduced with an adenoviral vector encoding CD40L (AdCD40L). The induced expression of co-stimulatory molecules and cell viability was analyzed. AdCD40L-transduced TRAMP-C2 cells were used in prophylactic vaccination studies, while therapeutic studies were performed using peritumoral injections of AdCD40L. RESULTS AdCD40L yielded reduced TRAMP-C2 cell viability and induced apoptosis in vitro. Vaccination with CD40L-expressing TRAMP-C2 cells induced anti-tumor immunity and peritumoral AdCD40L injections induced tumor growth suppression. CONCLUSIONS Our observations highlight the therapeutic potential of using AdCD40L as a monotherapy or in combination with conventional chemotherapy or novel therapies (e.g., oncolytic viruses). The use of AdCD40L offers an attractive option for future clinical trials.
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Affiliation(s)
- Helena Dzojic
- Clinical Immunology Division, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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