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Yang Y, Hu Y, Yang Y, Liu Q, Zheng P, Yang Z, Duan B, He J, Li W, Li D, Zheng X, Wang M, Fu Y, Long Q, Ma Y. Tumor Vaccine Exploiting Membranes with Influenza Virus-Induced Immunogenic Cell Death to Decorate Polylactic Coglycolic Acid Nanoparticles. ACS NANO 2025; 19:3115-3134. [PMID: 39806805 DOI: 10.1021/acsnano.4c00654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2). IAV-induced ICD cells enhance biomass-derived carbon (BMDCs) migration, antigen uptake, cross-presentation, and maturation in vitro. Furthermore, immunization with IAV-induced ICD cells effectively suppressed tumor growth in melanoma-bearing mice. The isolated cell membrane inherited the immunological characteristics from the ICD cells and elicited robust antitumor immune responses through decorating PLGA NPs loading with a tumor-specific helper T-cell peptide and supplemented with ATP in a hydrogel system. This study indicated a promising strategy for developing cell-based and personalized tumor vaccines through fully taking advantage of the immune stimulation mechanisms of ICD occurrence in tumor cells, IAV modification, and nanoscale delivery.
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Affiliation(s)
- Ying Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Yongmao Hu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Yunnan University, Kunming 650091, China
| | - Ying Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Kunming Medical University, Kunming 650500, China
| | - Qingwen Liu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Kunming Medical University, Kunming 650500, China
| | - Peng Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Zhongqian Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Biao Duan
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Kunming Medical University, Kunming 650500, China
| | - Jinrong He
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Weiran Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Duo Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- Department of Acute Infectious Diseases Control and Prevention, Yunnan Provincial Center for Disease Control and Prevention, Kunming 650000, China
| | - Xiao Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Mengzhen Wang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Yuting Fu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Qiong Long
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
| | - Yanbing Ma
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650031, China
- State Key Laboratory of Respiratory Health and Multimorbidity, Kunming 650031, China
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Yang X, Gao X, Xu C, Ni T, Sheng Y, Wang J, Sun X, Yuan J, Zhang L, Wang Y. Cryoablation synergizes with anti-PD-1 immunotherapy induces an effective abscopal effect in murine model of cervical cancer. Transl Oncol 2025; 51:102175. [PMID: 39489086 PMCID: PMC11565560 DOI: 10.1016/j.tranon.2024.102175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/15/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs), especially anti-PD-1/PD-L1 antibodies, have emerged as promising therapeutic options for cervical cancer. However, the efficacy of anti-PD-1 antibody monotherapy is limited. Cryoablation could elicit an anti-tumor immune response, thereby presenting itself as a potential approach to augment the response of ICIs. The aim of our study was to investigate the systemic immunological effects of cryoablation and the potential synergistic anti-tumor effects of cryoablation and anti-PD-1 antibody in cervical cancer. METHODS We established U14 murine bilateral subcutaneous cervical cancer model, wherein the primary tumors were treated with cryoablation. Flow cytometry, immunohistochemistry and RNA-seq were used to analyze the immune cell infiltration and immune-associated pathways in the secondary tumor. RESULTS Our study revealed that cryoablation reprogrammed the immune landscape, leading to an enhanced infiltration of CD8+ T cell in distant tumors. Cryoablation created a conducive environment for increasing the efficacy of anti-PD-1 immunotherapy. Cryoablation in combination with anti-PD-1 antibody inhibited distant tumors growth and improved mouse survival. Mechanistically, this combination therapy could augment the infiltration of CD8+ T cells, CD4+ T cells, dendritic cells and M1-like tumor-associated macrophages, enhance multiple aspects of antitumor immune response, and reduce immunosuppressive cells such as M2-like tumor-associated macrophages and myeloid-derived suppressor cells in distant tumors. CONCLUSIONS Combination therapy with cryoablation and anti-PD-1 antibody induces an effective abscopal effect in murine model of cervical cancer and may be a novel therapeutic approach for patients with advanced/recurrent cervical cancer.
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Affiliation(s)
- Xiaoming Yang
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Xiaoyan Gao
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Chen Xu
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Ting Ni
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yaru Sheng
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Jing Wang
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Xiao Sun
- Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Jiangjing Yuan
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Lin Zhang
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
| | - Yudong Wang
- Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Municipal Key Clinical Specialty of gynecologic oncology, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Padula L, Fisher E, Strbo N. "All for One and One for All": The Secreted Heat Shock Protein gp96-Ig Based Vaccines. Cells 2023; 13:72. [PMID: 38201276 PMCID: PMC10778431 DOI: 10.3390/cells13010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
It has been 50 years since Peter Charles Doherty and Rolf M Zinkernagel proposed the principle of "simultaneous dual recognition", according to which adaptive immune cells recognized "self" and "non-self" simultaneously to establish immunological efficacy. These two scientists shared the 1996 Nobel Prize in Physiology or Medicine for this discovery. Their basic immunological principle became the foundation for the development of numerous vaccine approaches against infectious diseases and tumors, including promising strategies grounded on the use of recombinant gp96-Ig developed by our lab over the last two decades. In this review, we will highlight three major principles of the gp96-Ig vaccine strategy: (1) presentation of pathogenic antigens to T cells (specificity); (2) activation of innate immune responses (adjuvanticity); (3) priming of T cells to home to the epithelial compartments (mucosal immunity). In summary, we provide a paradigm for a vaccine approach that can be rapidly engineered and customized for any future pathogens that require induction of effective tissue-resident memory responses in epithelial tissues.
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Affiliation(s)
| | | | - Natasa Strbo
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (L.P.); (E.F.)
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Zhang T, Aipire A, Li Y, Guo C, Li J. Antigen cross-presentation in dendric cells: From bench to bedside. Biomed Pharmacother 2023; 168:115758. [PMID: 37866002 DOI: 10.1016/j.biopha.2023.115758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/14/2023] [Accepted: 10/17/2023] [Indexed: 10/24/2023] Open
Abstract
Cross-presentation (XPT) is an adaptation of the cellular process in which dendritic cells (DCs) present exogenous antigens on major histocompatibility complex (MHC) class I molecules for recognition of the cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, resulting in immunity or tolerance. Recent advances in DCs have broadened our understanding of the underlying mechanisms of XPT and strengthened their application in tumor immunotherapy. In this review, we summarized the known mechanisms of XPT, including the receptor-mediated internalization of exogenous antigens, endosome escape, engagement of the other XPT-related proteins, and adjuvants, which significantly enhance the XPT capacity of DCs. Consequently, various strategies to enhance XPT can be adopted and optimized to improve outcomes of DC-based therapy.
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Affiliation(s)
- Tingting Zhang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China
| | - Adila Aipire
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China
| | - Yijie Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China
| | - Changying Guo
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China.
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China.
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Liu Q, Hu Y, Zheng P, Yang Y, Fu Y, Yang Y, Duan B, Wang M, Li D, Li W, He J, Zheng X, Long Q, Ma Y. Exploiting immunostimulatory mechanisms of immunogenic cell death to develop membrane-encapsulated nanoparticles as a potent tumor vaccine. J Nanobiotechnology 2023; 21:326. [PMID: 37684628 PMCID: PMC10492316 DOI: 10.1186/s12951-023-02031-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/28/2023] [Indexed: 09/10/2023] Open
Abstract
Vaccine is one of the most promising strategies for cancer immunotherapy; however, there are no therapeutic cancer vaccine achieving significant clinical efficacy till now. The main limiting factors include the immune suppression and escape mechanisms developed by tumor and not enough capacity of vaccines to induce a vigorous anti-tumor immunity. This study aimed to develop a strategy of membrane-based biomimetic nanovaccine and investigate the immunological outcomes of utilizing the unique immunostimulatory mechanisms derived of immunogenic cell death (ICD) and of fulfilling a simultaneous nanoscale delivery of a highlighted tumor antigen and broad membrane-associated tumor antigens in the vaccine design. TC-1 tumor cells were treated in vitro with a mixture of mitoxantrone and curcumin for ICD induction, and then chitosan (CS)-coated polylactic co-glycolic acid (PLGA) nanoparticles loaded with HPV16 E744-62 peptides were decorated with the prepared ICD tumor cell membrane (IM); further, the IM-decorated nanoparticles along with adenosine triphosphate (ATP) were embedded with sodium alginate (ALG) hydrogel, And then, the immunological features and therapeutic potency were evaluated in vitro and in vivo. The nanovaccine significantly stimulated the migration, antigen uptake, and maturation of DCs in vitro, improved antigen lysosome escape, and promoted the retention at injection site and accumulation in LNs of the tumor antigen in vivo. In a subcutaneously grafted TC-1 tumor model, the therapeutic immunization of nanovaccine elicited a dramatical antitumor immunity. This study provides a strategy for the development of tumor vaccines.
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Affiliation(s)
- Qingwen Liu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
- Institute of Medical Biology, Kunming Medical University, Kunming, 650500, China
| | - Yongmao Hu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
- School of Life Sciences, Yunnan University, Kunming, 650091, China
| | - Peng Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Ying Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Yuting Fu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Ying Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
- Institute of Medical Biology, Kunming Medical University, Kunming, 650500, China
| | - Biao Duan
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
- Institute of Medical Biology, Kunming Medical University, Kunming, 650500, China
| | - Mengzhen Wang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Duo Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Weiran Li
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Jinrong He
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Xiao Zheng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
- School of Life Sciences, Yunnan University, Kunming, 650091, China
| | - Qiong Long
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China
| | - Yanbing Ma
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, 650118, China.
- Institute of Medical Biology, Kunming Medical University, Kunming, 650500, China.
- School of Life Sciences, Yunnan University, Kunming, 650091, China.
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Abstract
The critical role of conventional dendritic cells in physiological cross-priming of immune responses to tumors and pathogens is widely documented and beyond doubt. However, there is ample evidence that a wide range of other cell types can also acquire the capacity to cross-present. These include not only other myeloid cells such as plasmacytoid dendritic cells, macrophages and neutrophils, but also lymphoid populations, endothelial and epithelial cells and stromal cells including fibroblasts. The aim of this review is to provide an overview of the relevant literature that analyzes each report cited for the antigens and readouts used, mechanistic insight and in vivo experimentation addressing physiological relevance. As this analysis shows, many reports rely on the exceptionally sensitive recognition of an ovalbumin peptide by a transgenic T cell receptor, with results that therefore cannot always be extrapolated to physiological settings. Mechanistic studies remain basic in most cases but reveal that the cytosolic pathway is dominant across many cell types, while vacuolar processing is most encountered in macrophages. Studies addressing physiological relevance rigorously remain exceptional but suggest that cross-presentation by non-dendritic cells may have significant impact in anti-tumor immunity and autoimmunity.
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Affiliation(s)
- François-Xavier Mauvais
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Service de Physiologie - Explorations Fonctionnelles Pédiatriques, AP-HP, Hôpital Universitaire Robert Debré, F-75019 Paris, France.
| | - Peter van Endert
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, F-75015 Paris, France.
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Li XP, Zhang J. A live attenuated Edwardsiella tarda vaccine induces immunological expression pattern in Japanese flounder (Paralichthys olivaceus) in the early phase of immunization. Comp Biochem Physiol C Toxicol Pharmacol 2021; 239:108872. [PMID: 32814144 DOI: 10.1016/j.cbpc.2020.108872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/03/2020] [Accepted: 08/09/2020] [Indexed: 12/29/2022]
Abstract
A previous study showed that an attenuated Edwardsiella tarda strain, TXhfq, as a live vaccine could elicit protective immune effects in fish against E. tarda infection. In the current study, in order to clarify the molecular mechanism of fish immune response at the early stage after TXhfq vaccination, RNA-Seq technology was used to compare the transcriptomes of skin, intestine, and spleen between bath-vaccinated and unvaccinated Japanese flounder (Paralichthys olivaceus). An average of 46.6 million clean reads per library was obtained, ~88.04% of which were successfully mapped to the reference genome, and approximately 24,600 genes were detected in each sample. A total of 565, 878, and 1258 differential expression genes (DEGs) were found in skin, intestine, and spleen, respectively, including 1263 up-regulated genes and 1438 down-regulated genes. The DEGs exhibited different characteristics in each tissue. One hundred and sixteen DEGs belonging to six immune related categories were scrutinized, i.e., inflammatory factors, cytokines, complement and coagulation system, mucins, phagocytosis, and antigen processing and presentation. A protein-protein interaction network was constructed to get the interaction network between immune genes during the early stage of immunization. The top six hub genes highly regulated by TXhfq formed complicated interaction relationship with each other, which were involved in immune processes, notably inflammation and phagocytosis. Our results provide valuable information for the understanding of the immune mechanism underlying the protection of live attenuated vaccines in fish.
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Affiliation(s)
- Xue-Peng Li
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; School of Ocean, Yantai University, Yantai, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Jian Zhang
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; School of Ocean, Yantai University, Yantai, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Zheng D, Wan C, Yang H, Xu L, Dong Q, Du C, Du J, Li F. Her2-Targeted Multifunctional Nano-Theranostic Platform Mediates Tumor Microenvironment Remodeling and Immune Activation for Breast Cancer Treatment. Int J Nanomedicine 2020; 15:10007-10028. [PMID: 33376321 PMCID: PMC7756023 DOI: 10.2147/ijn.s271213] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/16/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose The treatment of breast cancer is often ineffective due to the protection of the tumor microenvironment and the low immunogenicity of tumor cells, leading to a poor therapeutic effect. In this study, we designed a nano-theranostic platform for these obstacles: a photothermal effect mediated by a gold shell could remodel the tumor microenvironment by decreasing cancer-associated fibroblasts (CAFs) and promote the release of doxorubicin (DOX) from nanoparticles. In addition, it could realize photoacoustic (PA)/MRI dual-model imaging for diagnose breast cancer and targeted identification of Her2-positive breast cancer. Methods Her2-DOX-superparamagnetic iron oxide nanoparticles (SPIOs)@Poly (D, L-lactide-co-glycolide) acid (PLGA)@Au nanoparticles (Her2-DSG NPs) were prepared based on a single emulsion oil-in-water (O/W) solvent evaporation method, gold seed growing method, and carbon diimide method. The size distribution, morphology, PA/MRI imaging, drug loading capacity, and drug release were investigated. Cytotoxicity, antitumor effect, cellular uptake, immunogenic cell death (ICD) effect, and targeted performance on human Her2-positive BT474 cell line were investigated in vitro. BT474/Adr cells were constructed and the antitumor effect of NPs on it was evaluated in vitro. Moreover, chemical-photothermal therapy effect, PA/MRI dual-model imaging, ICD effect induced by NPs, and tumor microenvironment remodeling in human BT474 breast cancer nude mice model were also investigated. Results Nanoparticles were spherical, uniform in size and covered with a gold shell. NPs had a photothermal effect, and can realize photothermal-controlled drug release in vitro. Chemical-photothermal therapy had a good antitumor effect on BT474/Adr cells and on BT474 cells in vitro. The targeting evaluation in vitro showed that Her2-DSG NPs could actively target and identify Her2-positive tumor cells. The PA/MRI imaging was successfully validated in vitro/vivo. Similarly, NPs could enhance the ICD effect in vitro/vivo, which could activate an immune response. Immunofluorescence results also proved that photothermal effect could decrease CAFs to remodel the tumor microenvironment and enhance the accessibility of NPs to tumor cells. According to the toxicity results, targeted drug delivery combined with photothermal-responsive drug release proved that NPs had good biosafety in vivo. Chemical-photothermal therapy of Her2-targeted NPs has a good antitumor effect in the BT474 nude mice model. Conclusion Our study showed that chemical-photothermal therapy combined with tumor microenvironment remodeling and immune activation based on the Her2-DSG NPs we developed are very promising for Her2-positive breast cancer.
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Affiliation(s)
- Dongdong Zheng
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Caifeng Wan
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Hong Yang
- College of Chemistry and Materials Science, Shanghai Normal University, Shanghai, People's Republic of China
| | - Li Xu
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Qi Dong
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Chengrun Du
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Jing Du
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Fenghua Li
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
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Horak V, Palanova A, Cizkova J, Miltrova V, Vodicka P, Kupcova Skalnikova H. Melanoma-Bearing Libechov Minipig (MeLiM): The Unique Swine Model of Hereditary Metastatic Melanoma. Genes (Basel) 2019; 10:E915. [PMID: 31717496 PMCID: PMC6895830 DOI: 10.3390/genes10110915] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/31/2019] [Accepted: 11/07/2019] [Indexed: 12/12/2022] Open
Abstract
National cancer databases document that melanoma is the most aggressive and deadly cutaneous malignancy with worldwide increasing incidence in the Caucasian population. Around 10% of melanomas occur in families. Several germline mutations were identified that might help to indicate individuals at risk for preventive interventions and early disease detection. More than 50% of sporadic melanomas carry mutations in Ras/Raf/mitogen-activated protein kinase (MAPK/MEK) pathway, which may represent aims of novel targeted therapies. Despite advances in targeted therapies and immunotherapies, the outcomes in metastatic tumor are still unsatisfactory. Here, we review animal models that help our understanding of melanoma development and treatment, including non-vertebrate, mouse, swine, and other mammal models, with an emphasis on those with spontaneously developing melanoma. Special attention is paid to the melanoma-bearing Libechov minipig (MeLiM). This original swine model of hereditary metastatic melanoma enables studying biological processes underlying melanoma progression, as well as spontaneous regression. Current histological, immunohistochemical, biochemical, genetic, hematological, immunological, and skin microbiome findings in the MeLiM model are summarized, together with development of new therapeutic approaches based on tumor devitalization. The ongoing study of molecular and immunological base of spontaneous regression in MeLiM model has potential to bring new knowledge of clinical importance.
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Affiliation(s)
| | | | | | | | | | - Helena Kupcova Skalnikova
- Czech Academy of Sciences, Institute of Animal Physiology and Genetics, Laboratory of Applied Proteome Analyses and Research Center PIGMOD, 277 21 Libechov, Czech Republic; (V.H.); (A.P.); (J.C.); (V.M.); (P.V.)
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Srivastava PK, Callahan MK. Low-Level Inhibition of Hsp90 Forces Cells to Tip Their (Antigenic) Hand. Clin Cancer Res 2019; 25:6277-6279. [PMID: 31444251 DOI: 10.1158/1078-0432.ccr-19-2094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/22/2019] [Accepted: 08/21/2019] [Indexed: 11/16/2022]
Abstract
Low-level inhibition of hsp90 enhances the antigenicity of cells whereas high-level inhibition diminishes antigenicity. The mechanism(s) by which hsp90 determines antigenicity are only partially clear. Regardless, these observations have profound implications in protein trafficking and antigen presentation and suggest a novel way to enhance the potency of existing anticancer agents.See related article by Jaeger et al., p. 6392.
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Affiliation(s)
- Pramod K Srivastava
- Department of Immunology, and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, Connecticut.
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11
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Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion. Int J Mol Sci 2019; 20:ijms20184588. [PMID: 31533245 PMCID: PMC6770223 DOI: 10.3390/ijms20184588] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/13/2019] [Accepted: 09/14/2019] [Indexed: 12/17/2022] Open
Abstract
Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (α, β, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.
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12
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Yu K, Liang B, Zheng Y, Exner A, Kolios M, Xu T, Guo D, Cai X, Wang Z, Ran H, Chu L, Deng Z. PMMA-Fe 3O 4 for internal mechanical support and magnetic thermal ablation of bone tumors. Am J Cancer Res 2019; 9:4192-4207. [PMID: 31281541 PMCID: PMC6592182 DOI: 10.7150/thno.34157] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 05/09/2019] [Indexed: 12/28/2022] Open
Abstract
Background: Minimally invasive modalities are of great interest in the field of treating bone tumors. However, providing reliable mechanical support and fast killing of tumor cells to achieve rapid recovery of physical function is still challenging in clinical works. Methods: A material with two functions, mechanical support and magnetic thermal ablation, was developed from Fe3O4 nanoparticles (NPs) distributed in a polymethylmethacrylate (PMMA) bone cement. The mechanical properties and efficiency of magnetic field-induced thermal ablation were systematically and successfully evaluated in vitro and ex vivo. CT images and pathological examination were successfully applied to evaluate therapeutic efficacy with a rabbit bone tumor model. Biosafety evaluation was performed with a rabbit in vivo, and a cytotoxicity test was performed in vitro. Results: An NP content of 6% Fe3O4 (PMMA-6% Fe3O4, mFe: 0.01 g) gave the most suitable performance for in vivo study. At the 56-day follow-up after treatment, bone tumors were ablated without obvious side effects. The pathological examination and new bone formation in CT images clearly illustrate that the bone tumors were completely eliminated. Correspondingly, after treatment, the tendency of bone tumors toward metastasis significantly decreased. Moreover, with well-designed mechanical properties, PMMA-6%Fe3O4 implantation endowed tumor-bearing rabbit legs with excellent bio-mimic bone structure and internal support. Biosafety evaluation did not induce an increase or decrease in the immune response, and major functional parameters were all at normal levels. Conclusion: We have presented a novel, highly efficient and minimally invasive approach for complete bone tumor regression and bone defect repair by magnetic thermal ablation based on PMMA containing Fe3O4 NPs; this approach shows excellent heating ability for rabbit VX2 tibial plateau tumor ablation upon exposure to an alternating magnetic field (AMF) and provides mechanical support for bone repair. The new and powerful dual-function implant is a promising minimally invasive agent for the treatment of bone tumors and has good clinical translation potential.
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13
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Kaner Z, Engelman R, Schuster R, Rider P, Greenberg D, Av-Gay Y, Benhar M, Lewis EC. S-Nitrosylation of α1-Antitrypsin Triggers Macrophages Toward Inflammatory Phenotype and Enhances Intra-Cellular Bacteria Elimination. Front Immunol 2019; 10:590. [PMID: 31001247 PMCID: PMC6454134 DOI: 10.3389/fimmu.2019.00590] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/05/2019] [Indexed: 01/01/2023] Open
Abstract
Background: Human α1-antitrypsin (hAAT) is a circulating anti-inflammatory serine-protease inhibitor that rises during acute phase responses. in vivo, hAAT reduces bacterial load, without directly inhibiting bacterial growth. In conditions of excess nitric-oxide (NO), hAAT undergoes S-nitrosylation (S-NO-hAAT) and gains antibacterial capacity. The impact of S-NO-hAAT on immune cells has yet to be explored. Aim: Study the effects of S-NO-hAAT on immune cells during bacterial infection. Methods: Clinical-grade hAAT was S-nitrosylated and then compared to unmodified hAAT, functionally, and structurally. Intracellular bacterial clearance by THP-1 macrophages was assessed using live Salmonella typhi. Murine peritoneal macrophages were examined, and signaling pathways were evaluated. S-NO-hAAT was also investigated after blocking free mambranal cysteine residues on cells. Results: S-NO-hAAT (27.5 uM) enhances intracellular bacteria elimination by immunocytes (up to 1-log reduction). S-NO-hAAT causes resting macrophages to exhibit a pro-inflammatory and antibacterial phenotype, including release of inflammatory cytokines and induction of inducible nitric oxide synthase (iNOS) and TLR2. These pro-inflammatory effects are dependent upon cell surface thiols and activation of MAPK pathways. Conclusions: hAAT duality appears to be context-specific, involving S-nitrosylation in a nitric oxide rich environment. Our results suggest that S-nitrosylation facilitates the antibacterial activity of hAAT by promoting its ability to activate innate immune cells. This pro-inflammatory effect may involve transferring of nitric oxide from S-NO-hAAT to a free cysteine residue on cellular targets.
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Affiliation(s)
- Ziv Kaner
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Rotem Engelman
- Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Ronen Schuster
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Peleg Rider
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - David Greenberg
- The Pediatric Infectious Disease Unit, Soroka University Medical Center, Beer-Sheva, Israel
| | - Yossef Av-Gay
- Division of Infectious Diseases, Departments of Medicine and Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Moran Benhar
- Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Eli C Lewis
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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14
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Bekos C, Zimmermann M, Unger L, Janik S, Mitterbauer A, Koller M, Fritz R, Gäbler C, Didcock J, Kliman J, Klepetko W, Ankersmit HJ, Moser B. Exercise-induced bronchoconstriction, temperature regulation and the role of heat shock proteins in non-asthmatic recreational marathon and half-marathon runners. Sci Rep 2019; 9:4168. [PMID: 30862844 PMCID: PMC6414620 DOI: 10.1038/s41598-019-39983-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 02/07/2019] [Indexed: 12/17/2022] Open
Abstract
Exercise is the most common trigger of bronchospasm. Heat shock protein (HSP) expression was linked to asthmatic patients. The prevalence and pathophysiology of exercise-induced bronchoconstriction (EIB) in non-professional non-asthmatic runners is unknown. We sought to investigate the frequency of EIB and cytokine changes in non-professional non-asthmatic marathon and half marathoners with and without EIB. Testing was performed before the marathon (baseline), immediately post-marathon at the finish area (peak), and 2–7 days after the marathon (recovery): immunosorbent assays for measurement of HSP70, blood count analysis, spirometry and temperature measurements. We experienced a decline in FEV1 of ≥10% in 35.29% of marathon and 22.22% of half marathon runners. Runners with EIB had significantly higher HSP70 serum concentrations at baseline than those without EIB (987.4 ± 1486.7 vs. 655.6 ± 1073.9; p = 0.014). Marathoners with EIB had significantly increased WBC before participating in the competition (7.4 ± 1.7 vs. 6.0 ± 1.5; p = 0.021). After recovery we found increased HSP70 serum concentrations in marathoners with EIB compared to those without (2539.2 ± 1692.5 vs. 1237.2 ± 835.2; p = 0.032), WBC (7.6 ± 1.8 vs. 6.4 ± 1.6; p = 0.048) and PLT (273.0 ± 43.0 vs 237.2 ± 48.3; p = 0.040). At all measured skin sites skin temperatures in runners were significantly lower immediately after participating in the competition when compared to temperature before the race (skin temperature baseline vs. peak: abdominal: 33.1 ± 0.2 vs. 30.0 ± 0.4; p < 0.001; upper arm: 31.6 ± 0.2 vs. 29.4 ± 0.3; p < 0.001; upper leg: 30.7 ± 0.3 vs. 29.4 ± 0.2; p = 0.014; lower leg: 30.6 ± 1.0 vs. 30.2 ± 1.5; p = 0.007). We found a higher than expected number of non-professional athletes with EIB. HSP70 serum concentrations and elevated WBC could indicate a predisposition to EIB.
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Affiliation(s)
- Christine Bekos
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria.,Medical University of Vienna, Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Vienna, Austria
| | - Matthias Zimmermann
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria
| | - Lukas Unger
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria
| | - Stefan Janik
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria
| | - Andreas Mitterbauer
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria
| | | | - Robert Fritz
- Sportordination, Alserstraße 28, Vienna, Austria
| | | | - Jessica Didcock
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria
| | - Jonathan Kliman
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria
| | - Walter Klepetko
- Department of Surgery, Division of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - Hendrik Jan Ankersmit
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria.,Department of Surgery, Division of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - Bernhard Moser
- Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria. .,Department of Surgery, Division of Thoracic Surgery, Medical University Vienna, Vienna, Austria.
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15
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Immunotherapy, Radiotherapy, and Hyperthermia: A Combined Therapeutic Approach in Pancreatic Cancer Treatment. Cancers (Basel) 2018; 10:cancers10120469. [PMID: 30486519 PMCID: PMC6316720 DOI: 10.3390/cancers10120469] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/20/2018] [Accepted: 11/20/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PC) has the highest mortality rate amongst all other cancers in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of 8% for all stages of PC combined. The Whipple procedure, or pancreaticoduodenectomy, can increase survival for patients with resectable PC, however, less than 20% of patients are candidates for surgery at time of presentation. Most of the patients are diagnosed with advanced PC, often with regional and distant metastasis. In these advanced cases, chemotherapy and radiation have shown limited tumor control, and PC continues to be refractory to treatment and results in a poor survival outcome. In recent years, there has been intensive research on checkpoint inhibitor immunotherapy for PC, however, PC is characterized with dense stromal tissue and a tumor microenvironment (TME) that is highly immunosuppressive, which makes immunotherapy less effective. Interestingly, when immunotherapy is combined with radiation therapy (RT) and loco-regional hyperthermia (HT), it has demonstrated enhanced tumor responses. HT improves tumor killing via a variety of mechanisms, targeting both the tumor and the TME. Targeted HT raises the temperature of the tumor and surrounding tissues to 42–43 °C and makes the tumor more immunoresponsive. HT can also modulate the immune system of the TME by inducing and synthesizing heat shock proteins (HSP), which also activate an anti-tumor response. It is well known that HT can enhance RT-induced DNA damage in cancer cells and simultaneously help to oxygenate hypoxic regions. Thus, it is envisaged that combined HT and RT might have immunomodulatory effects in the PC-TME, making PC more responsive to immunotherapies. Moreover, the combined tripartite approach of immunotherapy, RT, and HT could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the immunotherapeutic effect of overall individual therapies to treat local and metastatic PC. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than monotherapy or dual therapy to treat and increase the survival of the PC patients.
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16
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Heat Shock Protein 70 Gene Single Nucleotide Polymorphism and Diabetic Foot Ulcer. Is There Any Relationship? J Clin Med 2018; 7:jcm7080187. [PMID: 30060485 PMCID: PMC6111513 DOI: 10.3390/jcm7080187] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/24/2018] [Accepted: 07/24/2018] [Indexed: 12/16/2022] Open
Abstract
Objective: The study aims to investigate the potential role of C2437T (Met493Thr) single nucleotide polymorphism (SNP) of the heat shock protein (HSP) 70 in diabetic foot ulcer patients. Methods: In this prospective cohort study, SNP of the HSP70 hom gene, also called HSPA1L, was studied among diabetic patients with an ulcer (Group A: n = 50), diabetic patients without an ulcer (Group B: n = 50), and healthy subjects (Group C: n = 50). Results: There was a higher frequency of T/T genotype in group A (76%) as compared to group B (44%) and group C (14%). Moreover, the frequency of T allele was 7.3% in group A, 5.5% in group B, and 3.9% in group C. C allele frequency was 2.6%, 4.4%, and 6.1% in group A, group B, and group C, respectively. In group A, the odds ratio and risk ratio were 19-fold and 5-fold, respectively, for the HSP70 hom T/T homozygous gene compared to B (OR 19.45; RR 5.42; X2 38.8, p < 0.0001). Moreover, 4-fold and 1.75-fold ratios have been compared with group C (OR 4.03; RR 1.72; X2 10.6, p < 0.001). No significant difference in genotype was observed in group B and group C. Conclusions: There is a significant and positive association of hspHSP70 hom polymorphism restricted to T allele in homozygous and heterozygous states among diabetic foot ulcer (DFU) patients.
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17
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Binder RJ. Immunosurveillance of cancer and the heat shock protein-CD91 pathway. Cell Immunol 2018; 343:103814. [PMID: 29784128 DOI: 10.1016/j.cellimm.2018.05.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/03/2018] [Accepted: 05/15/2018] [Indexed: 12/16/2022]
Abstract
The intracellular functions of heat shock proteins (HSPs) as chaperones of macromolecules are well known. Current observations point to a role of these chaperones in initiating and modulating immune responses to tumors via receptor(s) on dendritic cells. In this article we provide an insight into, and a basis for, the importance of these HSP-mediated immune responses in rejecting nascent and emerging tumors.
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Affiliation(s)
- Robert J Binder
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, United States.
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18
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Lin X, Wu X, Liu X. Temperature stress response of heat shock protein 90 (Hsp90) in the clam Paphia undulata. AQUACULTURE AND FISHERIES 2018. [DOI: 10.1016/j.aaf.2018.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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19
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Dabaghian M, Latifi AM, Tebianian M, NajmiNejad H, Ebrahimi SM. Nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-trimethyl chitosan (TMC) nanoparticulate systems: Preparation and immunogenicity in a mouse model. Vaccine 2018; 36:2886-2895. [PMID: 29627234 DOI: 10.1016/j.vaccine.2018.02.072] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 02/09/2018] [Accepted: 02/16/2018] [Indexed: 12/15/2022]
Abstract
In this study, the potential of N-trimethyl chitosan (TMC) nanoparticles as a carrier system for the nasal delivery of the r4M2e.HSP70c, as an M2e-based universal recombinant influenza virus vaccine candidate, was investigated in mice. The anti-M2e specific cellular and humoral immune responses were assessed and the protective efficacy against a 90% lethal dose (LD90) of influenza A/PR/8/34 (H1N1) in a mice model was evaluated. Our results showed that the intranasal immunization of mice with r4M2e.HSP70c+TMC rather than the control groups, r4M2e+TMC, r4M2e and PBS (Phosphate buffer saline), significantly elevated both longevity and serum level of the total M2e-specific IgG antibody with a significant shift in the IgG2a/IgG1 ratio toward IgG2a, induced a Th1 skewed humoral and cellular immune responses, increased IFN-γ, IgG, and IgA in the bronchoalveolar lavage fluid (BALF), and promoted the proliferation of peripheral blood lymphocytes with lower morbidity and mortality rate against viral challenge. In conclusion, based on evidence to our finding, nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-Trimethyl Chitosan (TMC) nanoparticulate system showed to induce a long lasting M2e-specific humoral and cellular immune responses and also provided full protection against a 90% lethal dose (LD90) of the influenza virus A/PR/8/34 (H1N1). It seems, protective immunity following intranasal administration of r4M2e could be resulted by the cooperation of both adjuvants, TMC and HSP70c.
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MESH Headings
- Adjuvants, Immunologic/administration & dosage
- Adjuvants, Immunologic/pharmacology
- Administration, Intranasal
- Animals
- Antibodies, Viral/analysis
- Bronchoalveolar Lavage Fluid/immunology
- Cell Proliferation
- Chitosan/administration & dosage
- Disease Models, Animal
- Drug Carriers/administration & dosage
- Female
- HSP72 Heat-Shock Proteins/administration & dosage
- HSP72 Heat-Shock Proteins/pharmacology
- Humans
- Immunity, Cellular
- Immunity, Humoral
- Immunoglobulin A/analysis
- Immunoglobulin G/analysis
- Influenza Vaccines/administration & dosage
- Influenza Vaccines/immunology
- Influenza, Human/prevention & control
- Interferon-gamma/analysis
- Leukocytes, Mononuclear/immunology
- Mice, Inbred BALB C
- Nanoparticles/administration & dosage
- Serum/immunology
- Survival Analysis
- Treatment Outcome
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/immunology
- Viral Matrix Proteins/administration & dosage
- Viral Matrix Proteins/immunology
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Affiliation(s)
- Mehran Dabaghian
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 14155-3651, Tehran, Iran; Biotechnology Department, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran
| | - Ali Mohammad Latifi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 14155-3651, Tehran, Iran
| | - Majid Tebianian
- Biotechnology Department, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran
| | - Hamid NajmiNejad
- Yazd University of Medical Sciences and Health Services, Department of Genetics and Molecular Medicine, Yazd, Iran
| | - Seyyed Mahmoud Ebrahimi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 14155-3651, Tehran, Iran.
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20
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Kelly M, McNeel D, Fisch P, Malkovsky M. Immunological considerations underlying heat shock protein-mediated cancer vaccine strategies. Immunol Lett 2017; 193:1-10. [PMID: 29129721 DOI: 10.1016/j.imlet.2017.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 11/01/2017] [Accepted: 11/05/2017] [Indexed: 12/31/2022]
Abstract
The success of active immunotherapies in the prevention of many infectious diseases over the course of over 200 years has lead scientists to wonder if the same principles could be applied to cancer. Antigen-specific active immunotherapies for the treatment of cancer have been researched for over two decades, however, the overwhelming majority of these studies have failed to stimulate robust clinical responses. It is clear that current active immunotherapy research should incorporate methods to increase the immunostimulatory capacity of these therapies. To directly address this need, we propose the addition of the immunostimulatory heat shock proteins (HSPs) to active immunotherapeutic strategies to augment their efficacy. Heat shock proteins are a family of highly conserved intracellular chaperone proteins, and are the most abundant family proteins inside cells. This ubiquity, and their robust immunostimulatory capacity, points to their importance in regulation of intracellular processes and, therefore, indicators of loss of cellular integrity if found extracellularly. Thus, we emphasize the importance of taking into consideration the location of vaccine-derived HSP/tumor-antigen complexes when designing active immunotheraputic strategies.
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Affiliation(s)
- Matthew Kelly
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Douglas McNeel
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Paul Fisch
- Universitätsklinikum Freiburg, Institut für Pathologie, Freiburg, Germany
| | - Miroslav Malkovsky
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA; Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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21
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Adkins I, Sadilkova L, Hradilova N, Tomala J, Kovar M, Spisek R. Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells. Oncoimmunology 2017. [PMID: 28638734 DOI: 10.1080/2162402x.2017.1311433] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42°C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43°C). Here, we found that sHS, but not mHS (42°C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1. Only sHS-treated tumor cells were efficiently killed and phagocytosed by dendritic cells (DCs), which was partially dependent on cell surface calreticulin. DCs loaded with mHS or sHS-treated tumor cells displayed similar level of maturation and stimulated IFNγ-producing CD8+ T cells without any additional adjuvants in vitro. However, only DCs loaded with sHS-treated tumor cells stimulated antigen-specific CD4+ T cells and induced higher CD8+ T-cell activation and proliferation. sHS-treated murine cells also exposed calreticulin, HSP70 and HSP90 and activated higher DC maturation than mHS treated cells. Vaccination with sHS-treated tumor cells elicited protective immunity in mice. In this study, we defined specific conditions for the sHS treatment of human lung and ovarian tumor cells to arrive at optimal ratio between effective cell death, immunogenicity and content of tumor antigens for immunotherapeutic vaccine generation.
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Affiliation(s)
- Irena Adkins
- Sotio a.s, Prague, Czech Republic.,Department of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | | | - Nada Hradilova
- Sotio a.s, Prague, Czech Republic.,Department of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Jakub Tomala
- Laboratory of Tumor Immunology, Institute of Microbiology of the ASCR v.v.i, Prague, Czech Republic
| | - Marek Kovar
- Laboratory of Tumor Immunology, Institute of Microbiology of the ASCR v.v.i, Prague, Czech Republic
| | - Radek Spisek
- Sotio a.s, Prague, Czech Republic.,Department of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
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22
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Pearce KF, Balavarca Y, Norden J, Jackson G, Holler E, Dressel R, Greinix H, Toubert A, Gluckman E, Hromadnikova I, Sedlacek P, Wolff D, Holtick U, Bickeböller H, Dickinson AM. Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia. Int J Immunogenet 2016; 43:404-412. [DOI: 10.1111/iji.12295] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 06/01/2016] [Accepted: 10/17/2016] [Indexed: 12/29/2022]
Affiliation(s)
- K. F. Pearce
- Haematological Sciences; Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne UK
| | - Y. Balavarca
- Department of Genetic Epidemiology; University Medical Center; Göttingen Germany
| | - J. Norden
- Haematological Sciences; Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne UK
| | - G. Jackson
- Northern Centre for Cancer Care; Newcastle upon Tyne Hospitals NHS Foundation Trust; Newcastle upon Tyne UK
| | - E. Holler
- Department of Internal Medicine III; University of Regensburg; Regensburg Germany
| | - R. Dressel
- Department of Cellular and Molecular Immunology; University Medical Center; Göttingen Germany
| | - H. Greinix
- Department of Internal Medicine; Division of Haematology; Medical University of Graz; Graz Austria
| | - A. Toubert
- Departement d′Immunologie; Université Paris Diderot; INSERM UMRS-940; AP-HP; Paris France
| | - E. Gluckman
- EUROCORD; University Research Institute; St Louis Hospital Paris France
| | - I. Hromadnikova
- Department of Molecular Biology and Cell Pathology; Third Faculty of Medicine; Charles University Prague; Prague Czech Republic
| | - P. Sedlacek
- Department of Pediatric Hematology and Oncology; Second Faculty of Medicine; Charles University Prague; Prague Czech Republic
| | - D. Wolff
- Department of Internal Medicine III; University of Regensburg; Regensburg Germany
| | - U. Holtick
- Department I of Internal Medicine; University of Cologne; Cologne Germany
| | - H. Bickeböller
- Department of Genetic Epidemiology; University Medical Center; Göttingen Germany
| | - A. M. Dickinson
- Haematological Sciences; Institute of Cellular Medicine; Newcastle University; Newcastle upon Tyne UK
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23
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Keehn A, Gartrell B, Schoenberg MP. Vesigenurtacel-L (HS-410) in the management of high-grade nonmuscle invasive bladder cancer. Future Oncol 2016; 12:2673-2682. [PMID: 27609194 DOI: 10.2217/fon-2016-0284] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Unlike other malignancies, the death rate of bladder cancer has not declined in several decades, highlighting the need for new treatment options. In the emerging era of immunotherapy, therapeutic cancer vaccines are an attractive option to cure, control and prevent cancer. Despite this, finding a feasible and efficacious vaccine platform has proven elusive across all malignancies. Vesigenurtacel-L is the first whole cell, allogeneic vaccine intended to treat high-grade, nonmuscle invasive bladder cancer. This type of vaccine technology for bladder cancer is novel, and has the potential to be both economically and logistically feasible.
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Affiliation(s)
- Aryeh Keehn
- Department of Urology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA
| | - Benjamin Gartrell
- Department of Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA
| | - Mark P Schoenberg
- Department of Urology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA
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24
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Tsan MF, Gao B. Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. ACTA ACUST UNITED AC 2016; 13:6-14. [PMID: 17621541 DOI: 10.1177/0968051907078604] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Extensive work in recent years has suggested that a number of endogenous molecules, their derivatives or degradation products may be potent activators of the innate immune system capable of inducing pro-inflammatory cytokine production by the monocyte—macrophage system and the activation and maturation of dendritic cells. The cytokine-like effects of these endogenous molecules are mediated via Toll-like receptor (TLR) signal transduction pathways in a manner similar to pathogen-associated molecular patterns (PAMPs). However, recent evidence suggests that the reported cytokine effects of some of these putative endogenous ligands are in fact due to contaminating PAMPs. The reasons for the failure to recognize PAMP contaminants being responsible for the putative TLR ligands of these endogenous molecules include: (i) failure to use highly purified preparations free of PAMP contamination; (ii) failure to recognize the heat sensitivity of lipopolysaccharide (LPS); and (iii) failure to consider contaminant(s) other than LPS. Strategies are proposed to avoid future designation of PAMP contamination as putative endogenous ligands of TLRs.
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Affiliation(s)
- Min-Fu Tsan
- Department of Veterans Affairs, Research Service, VA Medical Center, Washington, DC 20422, USA.
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25
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Hodges TR, Ferguson SD, Caruso HG, Kohanbash G, Zhou S, Cloughesy TF, Berger MS, Poste GH, Khasraw M, Ba S, Jiang T, Mikkelson T, Yung WKA, de Groot JF, Fine H, Cantley LC, Mellinghoff IK, Mitchell DA, Okada H, Heimberger AB. Prioritization schema for immunotherapy clinical trials in glioblastoma. Oncoimmunology 2016; 5:e1145332. [PMID: 27471611 DOI: 10.1080/2162402x.2016.1145332] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/12/2016] [Accepted: 01/16/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Emerging immunotherapeutic strategies for the treatment of glioblastoma (GBM) such as dendritic cell (DC) vaccines, heat shock proteins, peptide vaccines, and adoptive T-cell therapeutics, to name a few, have transitioned from the bench to clinical trials. With upcoming strategies and developing therapeutics, it is challenging to critically evaluate the practical, clinical potential of individual approaches and to advise patients on the most promising clinical trials. METHODS The authors propose a system to prioritize such therapies in an organized and data-driven fashion. This schema is based on four categories of factors: antigenic target robustness, immune-activation and -effector responses, preclinical vetting, and early evidence of clinical response. Each of these categories is subdivided to focus on the most salient elements for developing a successful immunotherapeutic approach for GBM, and a numerical score is generated. RESULTS The Score Card reveals therapeutics that have the most robust data to support their use, provides a reference prioritization score, and can be applied in a reiterative fashion with emerging data. CONCLUSIONS The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population.
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Affiliation(s)
- Tiffany R Hodges
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Sherise D Ferguson
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Hillary G Caruso
- The Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Gary Kohanbash
- Department of Neurosurgery, the University of California at San Francisco , San Francisco, USA
| | - Shouhao Zhou
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Timothy F Cloughesy
- Department of Neuro-Oncology, the University of California at Los Angeles , Los Angeles, CA, USA
| | - Mitchel S Berger
- Department of Neurosurgery, the University of California at San Francisco , San Francisco, USA
| | | | | | - Sujuan Ba
- The National Foundation for Cancer Research, Bethesda, MD, USA, Asian Fund for Cancer Research , Hong Kong, People's Republic of China
| | - Tao Jiang
- Department of Neurosurgery, Tiantan Hospital, Capital Medical University , Beijing, China
| | - Tom Mikkelson
- Department of Neurosurgery, Henry Ford Health System , Detroit, MI, USA
| | - W K Alfred Yung
- Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - John F de Groot
- Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Howard Fine
- Division of Neuro-Oncology, Weill Cornell Medical College , New York, NY, USA
| | - Lewis C Cantley
- Department of Systems Biology, Harvard Medical School , Boston, MA, USA
| | - Ingo K Mellinghoff
- Department of Neurology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , New York, NY, USA
| | - Duane A Mitchell
- Department of Neurosurgery, University of Florida , Gainesville, FL, USA
| | - Hideho Okada
- Department of Neurosurgery, the University of California at San Francisco , San Francisco, USA
| | - Amy B Heimberger
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
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26
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Abstract
Heat-shock protein 90 (HSP90) is a highly conserved molecular chaperone that plays prominent functional roles in nearly all aspects of cell biology. As a chaperone, it interacts with literally hundreds of "clients," many of which are important drivers, regulators, and promoters of cancer. Thus, HSP90 is a high-value target in the development of anticancer therapeutics. Despite its popularity, our overall knowledge of HSP90 in immune function has lagged behind its well-recognized tumor-supportive roles. The use of inhibitors of HSP90 as chemical biological probes has been invaluable in revealing important roles for the chaperone in multiple aspects of immune function. Given this critical link, we must now consider the question of how immune outcomes may be affected by the HSP90 inhibitors currently in clinical development for the treatment of cancer. This chapter will review some of the immunological aspects of HSP90 function in terms of its intracellular and extracellular roles in antigen presentation, immune effector cell tasks, and regulation of inflammatory processes. This review will further examine the value of HSP90 inhibitors within the context of cancer immunotherapy and will discuss how these drugs might be optimally utilized in combination with immune stimulatory approaches against cancer.
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27
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Abkin SV, Ostroumova OS, Komarova EY, Meshalkina DA, Shevtsov MA, Margulis BA, Guzhova IV. Phloretin increases the anti-tumor efficacy of intratumorally delivered heat-shock protein 70 kDa (HSP70) in a murine model of melanoma. Cancer Immunol Immunother 2016; 65:83-92. [PMID: 26646850 PMCID: PMC11028722 DOI: 10.1007/s00262-015-1778-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 11/19/2015] [Indexed: 10/22/2022]
Abstract
Recombinant HSP70 chaperone exerts a profound anticancer effect when administered intratumorally. This action is based on the ability of HSP70 to penetrate tumor cells and extract its endogenous homolog. To enhance the efficacy of HSP70 cycling, we employed phloretin, a flavonoid that enhances the pore-forming activity of the chaperone on artificial membranes. Phloretin increased the efficacy of HSP70 penetration in B16 mouse melanoma cells and K-562 human erythroblasts; this was accompanied with increased transport of the endogenous HSP70 to the plasma membrane. Importantly, treatment with HSP70 combined with phloretin led to the elevation of cell sensitivity to cytotoxic lymphocytes by 16-18 % compared to treatment with the chaperone alone. The incubation of K-562 cells with biotinylated HSP70 and phloretin increased the amount of the chaperone released from cells, suggesting that chaperone cycling could trigger a specific anti-tumor response. We studied the effect of the combination of HSP70 and phloretin using B16 melanoma and a novel method of HSP70-gel application. We found that the addition of phloretin to the gel reduced tumor weight almost fivefold compared with untreated mice, while the life span of the animals extended from 25 to 39 days. The increased survival was corroborated by the activation of innate and adaptive immunity; interestingly, HSP70 was more active in induction of CD8+ cell-mediated toxicity and γIFN production while phloretin contributed largely to the CD56+ cell response. In conclusion, the combination of HSP70 with phloretin could be a novel treatment for efficient immunotherapy of intractable cancers such as skin melanoma.
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Affiliation(s)
- Sergey V Abkin
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064
| | - Olga S Ostroumova
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064
| | - Elena Y Komarova
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064
| | - Darya A Meshalkina
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064
| | - Maxim A Shevtsov
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064
| | - Boris A Margulis
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064
| | - Irina V Guzhova
- Institute of Cytology of Russian Academy of Sciences, Tikhoretsky Prospect, 4, St. Petersburg, Russia, 194064.
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Abstract
Radiation therapy (RT) is a cornerstone in oncologic management and is employed in various curative and palliative scenarios for local-regional control. RT is thought to locally control tumor cells by direct physical DNA damage or indirect insults from reactive oxygen species. Therapeutic effects apart from those observed at the treatment target, that is, abscopal effect, have been observed for several decades, though the underlying mechanisms regulating this phenomenon have been unclear. Accumulating evidence now suggests that the immune system is a major determinant in regulating the abscopal effect. It is now evident that RT may also enhance immunologic responses to tumors by creating an in situ vaccine by eliciting antigen release from dying tumor cells. Harnessing the specificity and dynamic nature of the immune system to target tumors in conjunction with RT is an emerging field with much promise. To optimize this approach, it is important to systematically evaluate the intricacies of the host immune system, the new generation of immunotherapeutics and the RT approach. Here we will discuss the current biologic mechanisms thought to regulate the RT-induced abscopal effect and how these may be translated to the clinical setting.
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29
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Kobayashi T, Kakimi K, Nakayama E, Jimbow K. Antitumor immunity by magnetic nanoparticle-mediated hyperthermia. Nanomedicine (Lond) 2015; 9:1715-26. [PMID: 25321171 DOI: 10.2217/nnm.14.106] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Magnetic nanoparticle-mediated hyperthermia (MNHT) generates heat to a local tumor tissue of above 43°C without damaging surrounding normal tissues. By applying MNHT, a significant amount of heat-shock proteins is expressed within and around the tumor tissues, inducing tumor-specific immune responses. In vivo experiments have indicated that MNHT can induce the regression of not only a local tumor tissue exposed to heat, but also distant metastatic tumors unexposed to heat. In this article, we introduce recent progress in the application of MNHT for antitumor treatments and summarize the mechanisms and processes of its biological effects during antitumor induction by MNHT. Several clinical trials have been conducted indicating that the MNHT system may add a promising and novel approach to antitumor therapy.
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Affiliation(s)
- Takeshi Kobayashi
- Research Institute for Biological Functions, Chubu University, Matsumoto-cho 1200, Kasugai, Aichi 487-8501, Japan
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30
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Dabaghian M, Latifi AM, Tebianian M, Dabaghian F, Ebrahimi SM. A truncated C-terminal fragment of Mycobacterium tuberculosis HSP70 enhances cell-mediated immune response and longevity of the total IgG to influenza A virus M2e protein in mice. Antiviral Res 2015; 120:23-31. [PMID: 25989418 DOI: 10.1016/j.antiviral.2015.05.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/24/2015] [Accepted: 05/11/2015] [Indexed: 01/10/2023]
Abstract
As the importance of virus-specific IgG2a and strong induction of Th1 type immune response for virus clearance was reported, conventional influenza vaccines induce a highly humoral immune response and fail to induce cytotoxic T-lymphocyte (CTL) immunity. Hence, in agreement with heat shock protein 70 (HSP70) acting as Th1 cytokine-like adjuvant, an Escherichia coli-expressed r4M2e.HSP70c fusion protein comprising C-terminus of Mycobacterium tuberculosis HSP70 genetically fused to four tandem repeats of influenza A virus M2e was constructed. Then, the case-control study was carried out to evaluate the humoral and cellular responses elicited against M2e in Balb/C mice by intramuscular immunization with r4M2e.HSP70c alone. Our results showed that r4M2e.HSP70c rather than control groups, r4M2e, r4M2e+Alum, or rHSP70c, significantly elevated both longevity and serum level of the total M2e-specific IgG antibody, induced a Th1 skewed humoral and cellular immune responses, increased the level of IFN-γ in BALF, and promoted the proliferation of peripheral blood lymphocytes. Furthermore, a virus challenge experiment revealed that mice vaccinated with r4M2e.HSP70c limited the severity of influenza A disease by 100% survival rate, less sever body weight loss and delaying the onset of morbidity in mice for 2days rather than other control groups. Here, we used r4M2e.HSP70c to stimulate M2e-specific antibody and cellular immune responses in Balb/C mice. The mHSP70c in the fusion form induced a long lasting Th1 skewed humoral and cellular immune responses against its associated protein. It seems anti-M2e antibodies limit viral replication and ameliorate influenza infection that allows the immune system to induce sterilizing HA-antibody against whole virion that leads to full protection against virulent influenza infection.
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Affiliation(s)
- Mehran Dabaghian
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 14155-3651, Tehran, Iran; Department of Pathobiology, University of Tehran, Faculty of Veterinary Medicine, P.O. Box 14155-6453, Tehran, Iran
| | - Ali Mohammad Latifi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 14155-3651, Tehran, Iran
| | - Majid Tebianian
- Department of Biotechnology, Razi Vaccine and Serum Research Institute (RVSRI), P.O. Box 31975/148, Karaj, Tehran, Iran
| | - Fariba Dabaghian
- Department of Biotechnology, Razi Vaccine and Serum Research Institute (RVSRI), P.O. Box 31975/148, Karaj, Tehran, Iran
| | - Seyyed Mahmoud Ebrahimi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, P.O. Box 14155-3651, Tehran, Iran.
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31
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Zhang Y, Zhang Y, Chen J, Liu Y, Luo W. Dendritic-tumor fusion cells derived heat shock protein70-peptide complex has enhanced immunogenicity. PLoS One 2015; 10:e0126075. [PMID: 25961716 PMCID: PMC4427282 DOI: 10.1371/journal.pone.0126075] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/28/2015] [Indexed: 12/02/2022] Open
Abstract
Tumor-derived heat shock protein70-peptide complexes (HSP70.PC-Tu) have shown great promise in tumor immunotherapy due to numerous advantages. However, large-scale phase III clinical trials showed that the limited immunogenicity remained to be enhanced. In previous research, we demonstrated that heat shock protein 70-peptide complexes (HSP70.PC-Fc) derived from dendritic cell (DC)-tumor fusions exhibit enhanced immunogenicity compared with HSP70.PCs from tumor cells. However, the DCs used in our previous research were obtained from healthy donors and not from the patient population. In order to promote the clinical application of these complexes, HSP70.PC-Fc was prepared from patient-derived DC fused directly with patient-derived tumor cells in the current study. Our results showed that compared with HSP70.PC-Tu, HSP70.PC-Fc elicited much more powerful immune responses against the tumor from which the HSP70 was derived, including enhanced T cell activation, and CTL responses that were shown to be antigen specific and HLA restricted. Our results further indicated that the enhanced immunogenicity is related to the activation of CD4+ T cells and increased association with other heat shock proteins, such as HSP90. Therefore, the current study confirms the enhanced immunogenicity of HSP70.PC derived from DC-tumor fusions and may provide direct evidence promoting their future clinical use.
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Affiliation(s)
- Yunfei Zhang
- Department of Orthopaedic, Orthopaedic Oncology Institute of PLA, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi’an, Shaanxi Province, China
| | - Yong Zhang
- Department of Orthopaedic, Orthopaedic Oncology Institute of PLA, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi’an, Shaanxi Province, China
| | - Jun Chen
- Department of Orthopaedic, Orthopaedic Oncology Institute of PLA, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi’an, Shaanxi Province, China
| | - Yunyan Liu
- Department of Orthopaedic, Orthopaedic Oncology Institute of PLA, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi’an, Shaanxi Province, China
| | - Wen Luo
- Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Changle Road, Xi’an, Shaanxi Province, China
- * E-mail:
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32
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Tyagi N, Tyagi R. The wonderous chaperones: A highlight on therapeutics of cancer and potentially malignant disorders. J Oral Maxillofac Pathol 2015; 19:212-20. [PMID: 26604499 PMCID: PMC4611931 DOI: 10.4103/0973-029x.164535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 07/06/2015] [Indexed: 12/21/2022] Open
Abstract
Diverse environmental and physiological factors are known to induce the transcription of a set of genes encoding special protective molecules known as "molecular chaperones" within our cells. Literature abounds in evidence regarding the varied roles; these "guides" can effectively perform in our system. Highly conserved through evolution, from the prokaryotes to the eukaryotes, these make perfect study tools for verifying their role in both the pathogenesis as well as the therapeutics of varied neurodegenerative, autoimmune and potentially malignant disorders and varied cancer states. We present a concise review of this ever dynamic molecule, highlighting the probable role in a potentially malignant disorder, oral lichen planus.
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Affiliation(s)
- Nutan Tyagi
- Department of Oral and Maxillofacial Pathology, Institute of Dental Studies and Technologies, NH-58, Kadrabad, Modinagar, New Delhi, India
| | - Rishi Tyagi
- Department of Pedodontics and Preventive Dentistry, University of Delhi, University College of Medical Sciences and GTB Hospital, Dilshad Garden, New Delhi, India
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33
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Is there any relationship between polymorphism of Heat Shock Protein 70 genes and Pemphigus foliaceus? Immunol Lett 2015; 164:94-9. [DOI: 10.1016/j.imlet.2015.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Revised: 01/16/2015] [Accepted: 01/23/2015] [Indexed: 11/22/2022]
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34
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Binder RJ. Functions of heat shock proteins in pathways of the innate and adaptive immune system. THE JOURNAL OF IMMUNOLOGY 2015; 193:5765-71. [PMID: 25480955 DOI: 10.4049/jimmunol.1401417] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
For more than 50 years, heat shock proteins (HSPs) have been studied for their role in protecting cells from elevated temperature and other forms of stress. More recently, several roles have been ascribed to HSPs in the immune system. These include intracellular roles in Ag presentation and expression of innate receptors, as well as extracellular roles in tumor immunosurveillance and autoimmunity. Exogenously administered HSPs can elicit a variety of immune responses that have been used in immunotherapy of cancer, infectious diseases, and autoimmune disease.
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Affiliation(s)
- Robert Julian Binder
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
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35
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Morris G, Berk M, Galecki P, Walder K, Maes M. The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases. Mol Neurobiol 2015; 53:1195-1219. [PMID: 25598355 DOI: 10.1007/s12035-015-9090-9] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 01/05/2015] [Indexed: 01/18/2023]
Abstract
Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.
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Affiliation(s)
- Gerwyn Morris
- Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, UK
| | - Michael Berk
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia.,Orygen Youth Health Research Centre and the Centre of Youth Mental Health, Poplar Road 35, Parkville, 3052, Australia.,The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Kenneth Myer Building, Royal Parade 30, Parkville, 3052, Australia.,Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, Parkville, 3052, Australia
| | - Piotr Galecki
- Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
| | - Ken Walder
- Metabolic Research Unit, Deakin University, Geelong, Australia
| | - Michael Maes
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia. .,Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. .,Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil. .,Impact Strategic Research Center, Deakin University, Geelong, Australia.
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36
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Graner MW, Lillehei KO, Katsanis E. Endoplasmic reticulum chaperones and their roles in the immunogenicity of cancer vaccines. Front Oncol 2015; 4:379. [PMID: 25610811 PMCID: PMC4285071 DOI: 10.3389/fonc.2014.00379] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/17/2014] [Indexed: 11/25/2022] Open
Abstract
The endoplasmic reticulum (ER) is a major site of passage for proteins en route to other organelles, to the cell surface, and to the extracellular space. It is also the transport route for peptides generated in the cytosol by the proteasome into the ER for loading onto major histocompatibility complex class I (MHC I) molecules for eventual antigen presentation at the cell surface. Chaperones within the ER are critical for many of these processes; however, outside the ER certain of those chaperones may play important and direct roles in immune responses. In some cases, particular ER chaperones have been utilized as vaccines against tumors or infectious disease pathogens when purified from tumor tissue or recombinantly generated and loaded with antigen. In other cases, the cell surface location of ER chaperones has implications for immune responses as well as possible tumor resistance. We have produced heat-shock protein/chaperone protein-based cancer vaccines called “chaperone-rich cell lysate” (CRCL) that are conglomerates of chaperones enriched from solid tumors by an isoelectric focusing technique. These preparations have been effective against numerous murine tumors, as well as in a canine with an advanced lung carcinoma treated with autologous CRCL. We also published extensive proteomic analyses of CRCL prepared from human surgically resected tumor samples. Of note, these preparations contained at least 10 ER chaperones and a number of other residents, along with many other chaperones/heat-shock proteins. Gene ontology and network analyses utilizing these proteins essentially recapitulate the antigen presentation pathways and interconnections. In conjunction with our current knowledge of cell surface/extracellular ER chaperones, these data collectively suggest that a systems-level view may provide insight into the potent immune stimulatory activities of CRCL with an emphasis on the roles of ER components in those processes.
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Affiliation(s)
- Michael W Graner
- Department of Neurosurgery, Anschutz Medical Campus, University of Colorado School of Medicine , Aurora, CO , USA
| | - Kevin O Lillehei
- Department of Neurosurgery, Anschutz Medical Campus, University of Colorado School of Medicine , Aurora, CO , USA
| | - Emmanuel Katsanis
- Department of Pediatrics, The University of Arizona , Tucson, AZ , USA
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Rödel F, Frey B, Multhoff G, Gaipl U. Contribution of the immune system to bystander and non-targeted effects of ionizing radiation. Cancer Lett 2015; 356:105-13. [DOI: 10.1016/j.canlet.2013.09.015] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 08/13/2013] [Accepted: 09/11/2013] [Indexed: 12/21/2022]
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Wang H, Zhang L, Shi Y, Javidiparsijani S, Wang G, Li X, Ouyang W, Zhou J, Zhao L, Wang X, Zhang X, Gao F, Liu J, Luo J, Tang J. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats. Oncol Lett 2014; 7:764-770. [PMID: 24527084 PMCID: PMC3919910 DOI: 10.3892/ol.2014.1803] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 12/20/2013] [Indexed: 11/11/2022] Open
Abstract
The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42–46°C and 50–55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50–55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.
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Affiliation(s)
- Hui Wang
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China ; Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Li Zhang
- Department of Engineering Physics, Tsinghua University Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Haidian, Beijing 100084, P.R. China
| | - Yingrui Shi
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | | | - Guirong Wang
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Xiao Li
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Weiwei Ouyang
- Department of Thoracic Oncology, Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Jumei Zhou
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lingyun Zhao
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiaowen Wang
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiaodong Zhang
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Fuping Gao
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingshi Liu
- Department of Anesthesiology, Hunan Provincial Tumor Hospital, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan 410013, P.R. China
| | - Junming Luo
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China ; Department of Pathology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Jintian Tang
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
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Strbo N, Garcia-Soto A, Schreiber TH, Podack ER. Secreted heat shock protein gp96-Ig: next-generation vaccines for cancer and infectious diseases. Immunol Res 2013; 57:311-25. [PMID: 24254084 DOI: 10.1007/s12026-013-8468-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Over the past decade, our laboratory has developed a secreted heat shock protein (HSP), chaperone gp96, cell-based vaccine that generates effective anti-tumor and anti-infectious immunity in vivo. Gp96-peptide complexes were identified as an extremely efficient stimulator of MHC I-mediated antigen cross-presentation, generating CD8 cytotoxic T-lymphocyte responses detectable in blood, spleen, gut and reproductive tract to femto-molar concentrations of antigen. These studies provided the first evidence that cell-based gp96-Ig-secreting vaccines may serve as a potent modality to induce both systemic and mucosal immunity. This approach takes advantage of the combined adjuvant and antigen delivery capacity of gp96 for the generation of cytotoxic immunity against a wide range of antigens in both anti-vial and anti-cancer vaccination. Here, we review the vaccine design that utilizes the unique property/ability of endoplasmic HSP gp96 to bind antigenic peptides and deliver them to antigen-presenting cells.
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Affiliation(s)
- Natasa Strbo
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, RMSB 3008, 1600 NW 10th Ave, Miami, FL, 33136, USA,
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D’Eliseo D, Manzi L, Velotti F. Capsaicin as an inducer of damage-associated molecular patterns (DAMPs) of immunogenic cell death (ICD) in human bladder cancer cells. Cell Stress Chaperones 2013; 18:801-8. [PMID: 23580156 PMCID: PMC3789874 DOI: 10.1007/s12192-013-0422-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 03/15/2013] [Accepted: 03/18/2013] [Indexed: 01/08/2023] Open
Abstract
Few conventional cytotoxic anticancer therapeutics induce immunogenic cell death (ICD). This means that they induce tumor cells to undergo apoptosis while eliciting the emission of a spatiotemporal-defined combination of damage-associated molecular patterns (DAMPs) decoded by the immune system to activate antitumor immunity effective for long-term therapeutic success. The neurotoxin capsaicin (CPS) can induce both cancer cell apoptosis and immune-mediated tumor regression. In the present study, we investigated whether CPS is capable of eliciting the emission of ICD hallmarks in human bladder cancer cell lines undergoing apoptosis. We demonstrated that CPS induces pre- and early apoptotic cell surface exposure of calreticulin (CRT), HSP90, and HSP70 as well as ATP release. Moreover, CRT exposure was prevented by inhibition of endoplasmic reticulum-Golgi traffic by brefeldin A. Furthermore, high-mobility group box 1, HSP90, and HSP70 were passively released at late apoptotic stages. We provide the first evidence that CPS is an inducer of ICD hallmarks, suggesting CPS as a novel potential immunogenic cytotoxic agent.
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Affiliation(s)
- Donatella D’Eliseo
- Department of Ecological and Biological Sciences (DEB), University of La Tuscia, Largo dell’Università, Blocco C, 01100 Viterbo, Italy
| | - Laura Manzi
- Department of Ecological and Biological Sciences (DEB), University of La Tuscia, Largo dell’Università, Blocco C, 01100 Viterbo, Italy
| | - Francesca Velotti
- Department of Ecological and Biological Sciences (DEB), University of La Tuscia, Largo dell’Università, Blocco C, 01100 Viterbo, Italy
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Messmer MN, Pasmowitz J, Kropp LE, Watkins SC, Binder RJ. Identification of the cellular sentinels for native immunogenic heat shock proteins in vivo. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2013; 191:4456-65. [PMID: 24048898 PMCID: PMC3801103 DOI: 10.4049/jimmunol.1300827] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Select members of the heat shock proteins (HSPs) family, such as gp96, elicit immune responses specific to their chaperoned peptides. Although immunologic effects of HSPs on APCs described to date have largely been demonstrated with cell lines or primary cells in culture, their collective responses in vitro have been consistent with priming immune responses. In this study, we examine the physiologically relevant APCs in mice that are targeted after vaccination with native, murine HSPs, and we characterize those cells. Gp96 accesses the subcapsular region of the draining lymph node, and it is internalized predominantly by CD11b(+) cells in this locale. Cells acquiring gp96 can transfer protective antitumor immunity to naive mice by actively cross-presenting gp96-chaperoned peptides and providing costimulation. Our studies illustrate how HSPs act to alert the immune system of cellular damage and will be of paramount importance in immunotherapy of patients with cancer and infectious disease.
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Zhang Y, Zheng L. Tumor immunotherapy based on tumor-derived heat shock proteins (Review). Oncol Lett 2013; 6:1543-1549. [PMID: 24260044 PMCID: PMC3834116 DOI: 10.3892/ol.2013.1616] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 09/25/2013] [Indexed: 12/28/2022] Open
Abstract
Heat shock proteins (HSPs), the most important type of molecular chaperone, are expressed in all eukaryotic cells and have multiple functions, including the folding and unfolding of other proteins and peptides, the transport of proteins and peptides and the support of antigen presentation processes. Due to these important properties, the use of HSPs has been explored as a promising tumor immunotherapy strategy. It has been previously demonstrated that HSP peptide complex (HSP.PC) derived from tumors is the immunogenic entity that elicits powerful antitumor immune responses. Previous animal studies and phase III clinical trials have demonstrated the efficacy, safety and feasibility of HSP-based tumor vaccines. However, the limitations are also apparent and specific alternatives have been developed. The present review focused on the history of HSP-based immunotherapy, the mechanism of its immunogenicity and the previous efforts to promote the efficacy. The current review may be useful for antitumor studies based on the tumor-derived HSPs.
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Affiliation(s)
- Yunfei Zhang
- Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
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Zong J, Wang C, Wang Q, Peng Q, Xu Y, Xie X, Xu X. HSP70 and modified HPV 16 E7 fusion gene without the addition of a signal peptide gene sequence as a candidate therapeutic tumor vaccine. Oncol Rep 2013; 30:3020-6. [PMID: 24065282 DOI: 10.3892/or.2013.2742] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 09/06/2013] [Indexed: 11/06/2022] Open
Abstract
Millions of women are currently infected with high-risk human papillomavirus (HPV), which is considered to be a major risk factor for cervical cancer. Thus, it is urgent to develop therapeutic vaccines to eliminate the established infections or HPV-related diseases. In the present study, using the mycobacterium tuberculosis heat shock protein 70 (MtHSP70) gene linked to the modified HPV 16 E7 (mE7) gene, we generated two potential therapeutic HPV DNA vaccines, mE7/MtHSP70 and SigmE7/MtHSP70, the latter was linked to the signal peptide gene sequence of human CD33 at the upstream of the fusion gene. We found that vaccination with the mE7/MtHSP70 DNA vaccine induced a stronger E7-specific CD8+ T cell response and resulted in a more significant therapeutic effect against E7-expressing tumor cells in mice. Our results demonstrated that HSP70 can play a more important role in mE7 and MtHSP70 fusion DNA vaccine without the help of a signal peptide. This may facilitate the use of HSP70 and serve as a significant reference for future study.
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Affiliation(s)
- Jinbao Zong
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing 100005, P.R. China
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Jackson C, Ruzevick J, Brem H, Lim M. Vaccine strategies for glioblastoma: progress and future directions. Immunotherapy 2013; 5:155-67. [PMID: 23413907 DOI: 10.2217/imt.12.155] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Recent advances in glioblastoma therapy have led to optimism that more effective therapies will improve outcomes. Immunotherapy is a promising approach that has demonstrated the potential to eradicate cancer cells with cellular-level accuracy while minimizing damage to surrounding healthy tissue. Several vaccination strategies have been evaluated for activity against glioblastoma in clinical trials. These include peptide vaccines, polyvalent dendritic cell vaccines, heat shock protein vaccines and adoptive immunotherapy. In this review, we highlight clinical trials representative of each of these approaches and discuss strategies for integrating these therapies into routine patient care.
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Affiliation(s)
- Christopher Jackson
- The Johns Hopkins Hospital, Department of Neurosurgery, Baltimore, MD 21287, USA
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McNulty S, Colaco CA, Blandford LE, Bailey CR, Baschieri S, Todryk S. Heat-shock proteins as dendritic cell-targeting vaccines--getting warmer. Immunology 2013; 139:407-15. [PMID: 23551234 PMCID: PMC3719058 DOI: 10.1111/imm.12104] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 02/08/2013] [Accepted: 02/15/2013] [Indexed: 12/22/2022] Open
Abstract
Heat-shock proteins (hsp) provide a natural link between innate and adaptive immune responses by combining the ideal properties of antigen carriage (chaperoning), targeting and activation of antigen-presenting cells (APC), including dendritic cells (DC). Targeting is achieved through binding of hsp to distinct cell surface receptors and is followed by antigen internalization, processing and presentation. An improved understanding of the interaction of hsp with DC has driven the development of numerous hsp-containing vaccines, designed to deliver antigens directly to DC. Studies in mice have shown that for cancers, such vaccines generate impressive immune responses and protection from tumour challenge. However, translation to human use, as for many experimental immunotherapies, has been slow partly because of the need to perform trials in patients with advanced cancers, where demonstration of efficacy is challenging. Recently, the properties of hsp have been used for development of prophylactic vaccines against infectious diseases including tuberculosis and meningitis. These hsp-based vaccines, in the form of pathogen-derived hsp-antigen complexes, or recombinant hsp combined with selected antigens in vitro, offer an innovative approach against challenging diseases where broad antigen coverage is critical.
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Affiliation(s)
- Shaun McNulty
- ImmunoBiology Ltd., Babraham Research Campus, Babraham, Cambridge, UK.
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Dong L, Zhang X, Ren J, Wu S, Yu T, Hou L, Fu L, Yi S, Yu C. Human Prostate Stem Cell Antigen and HSP70 Fusion Protein Vaccine Inhibits Prostate Stem Cell Antigen-Expressing Tumor Growth in Mice. Cancer Biother Radiopharm 2013; 28:391-7. [DOI: 10.1089/cbr.2012.1357] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Lei Dong
- Clinical Laboratory Center, PLA Air Force General Hospital, Beijing, China
| | - Xiaopeng Zhang
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Jun Ren
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Shipo Wu
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Ting Yu
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Lihua Hou
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Ling Fu
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Shaoqiong Yi
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Changming Yu
- Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
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Dong L, Zhang X, Yu C, Ren J, Hou L, Fu L, Yi S, Chen W. Expression and purification of recombinant proteins based on human prostate stem cell antigen and heat shock protein-70. Exp Ther Med 2013; 5:1161-1164. [PMID: 23596484 PMCID: PMC3627452 DOI: 10.3892/etm.2013.967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 02/05/2013] [Indexed: 11/20/2022] Open
Abstract
The aim of this study was to express and purify recombinant proteins based on human prostate stem cell antigen (PSCA) and heat shock protein-70 (HSP70). The PSCA gene and various structural domains of HSP70 were amplified by polymerase chain reaction (PCR) with the respective primers. Then, the PSCA was cloned into the prokaryotic expression vector pET21a(+) with the amino-terminus, carboxyl-terminus and overall length of HSP70, by enzyme digestion to construct the recombinant plasmids pET21-PSCA-HSPN, pET21-PSCA-HSPC and pET21-PSCA-HSP, respectively. After being expressed in Escherichia coli (E. coli) by isopropyl β-D-1-thiogalactopyranoside (IPTG) induction, recombinant fusion proteins were purified. Western blotting was performed to confirm the expression of the recombinant proteins. The results revealed that recombinant plasmids were successfully constructed. The PSCA-HSPC and PSCA-HSP expressed in E. coli existed in soluble form, as confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The purity of the recombinant proteins PSCA-HSPC and PSCA-HSP reached >95% following purification with the nickel-nitrilotriacetic acid (Ni-NTA) resin, Phenyl-Sepharose Fast Flow and Superdex 75, which lays a foundation for the development of vaccines for prostate cancer.
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Affiliation(s)
- Lei Dong
- Clinical Laboratory Center, PLA Air Force General Hospital, Haidian, Beijing 100142, P.R. China
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Abstract
Graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation. Many genes are presumed to be involved in GVHD, but the best characterized genetic system is that of the human major histocompatibility complex (MHC) located on chromosome 6. Among the hundreds of genes located within the MHC region, the best known and characterized are the classical HLA genes, HLA-A, C, B, DRB1, DQB1, and DPB1. They play a fundamental role in T cell immune responses, and HLA-A, C, and B also function as ligands for the natural killer cell immunoglobulin-like receptors involved in innate immunity. This review highlights the state-of-the art in the field of histocompatibility and immunogenetics of the MHC with respect to genetic risk factors for GVHD.
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CD91-Dependent Modulation of Immune Responses by Heat Shock Proteins: A Role in Autoimmunity. Autoimmune Dis 2012; 2012:863041. [PMID: 23209886 PMCID: PMC3507052 DOI: 10.1155/2012/863041] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 10/15/2012] [Indexed: 02/04/2023] Open
Abstract
Heat shock proteins (HSPs) have been known for decades for their ability to protect cells under stressful conditions. In the 1980s a new role was ascribed for several HSPs given their ability to elicit specific immune responses in the setting of cancer and infectious disease. These immune responses have primarily been harnessed for the immunotherapy of cancer in the clinical setting. However, because of the ability of HSPs to prime diverse immune responses, they have also been used for modulation of immune responses during autoimmunity. The apparent dichotomy of immune responses elicited by HSPs is discussed here on a molecular and cellular level. The potential clinical application of HSP-mediated immune responses for therapy of autoimmune diseases is reviewed.
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Heat Shock Protein-Peptide Complexes as Therapeutic Vaccines against Human Cancer. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03259498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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