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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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Cascio P. PA28γ, the ring that makes tumors invisible to the immune system? Biochimie 2024; 226:136-147. [PMID: 38631454 DOI: 10.1016/j.biochi.2024.04.003] [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: 02/07/2024] [Revised: 03/29/2024] [Accepted: 04/12/2024] [Indexed: 04/19/2024]
Abstract
PA28γ is a proteasomal interactor whose main and most known function is to stimulate the hydrolytic activity of the 20 S proteasome independently of ubiquitin and ATP. Unlike its two paralogues, PA28α and PA28β, PA28γ is largely present in the nuclear compartment and plays pivotal functions in important pathways such as cellular division, apoptosis, neoplastic transformation, chromatin structure and organization, fertility, lipid metabolism, and DNA repair mechanisms. Although it is known that a substantial fraction of PA28γ is found in the cell in a free form (i.e. not associated with 20 S), almost all of the studies so far have focused on its ability to modulate proteasomal enzymatic activities. In this respect, the ability of PA28γ to strongly stimulate degradation of proteins, especially if intrinsically disordered and therefore devoid of three-dimensional tightly folded structure, appears to be the main molecular mechanism underlying its multiple biological effects. Initial studies, conducted more than 20 years ago, came to the conclusion that among the many biological functions of PA28γ, the immunological ones were rather limited and circumscribed. In this review, we focus on recent evidence showing that PA28γ fulfills significant functions in cell-mediated acquired immunity, with a particular role in attenuating MHC class I antigen presentation, especially in relation to neoplastic transformation and autoimmune diseases.
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Affiliation(s)
- Paolo Cascio
- Department of Veterinary Sciences, University of Turin, Largo P. Braccini 2, 10095, Grugliasco, Turin, Italy.
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Lee MS, Park SM, Kim YJ. Photothermal treatment-based heat stress regulates function of myeloid-derived suppressor cells. Sci Rep 2024; 14:18847. [PMID: 39143087 PMCID: PMC11324874 DOI: 10.1038/s41598-024-69074-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/31/2024] [Indexed: 08/16/2024] Open
Abstract
Photothermal therapy is an alternative cancer therapy that uses a photothermal agent with light irradiation to induce fatal hyperthermia in cancer cells. In a previous study, we found that ex vivo photothermal (PT) treatment induced expression of heat shock proteins (HSPs), such as HSP70, HSP27, and HSP90, in cancer cells; moreover, immunization with lysates from PT-treated tumor cells resulted in significant tumor growth inhibition in tumor-bearing mice. In this study, we hypothesized that sublethal PT treatment of antigen-presenting cells regulates their immunogenicity. We observed the upregulation of expression of intracellular HSP70 and surface activation markers, such as CD40, CD80, CD86, and MHC class II, in sublethal PT-treated cells. The protumoral activity of myeloid-derived suppressor cells (MDSCs) was reduced by sublethal hyperthermia. Furthermore, poorly immunogenic MDSCs were converted into immunogenic antigen-presenting cells by PT treatment. The differences in immunogenicity between MDSCs untreated or treated with the PT technique were evaluated using the Student's t-test or Mann-Whitney rank sum test. Collectively, direct hyperthermic treatment resulted in phenotypic changes and the functional regulation of immune cells.
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Affiliation(s)
- Min-Seob Lee
- Laboratory of Microbiology and Immunology, College of Pharmacy, Inje University, 197, Inje-Ro, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Seon Mi Park
- Laboratory of Microbiology and Immunology, College of Pharmacy, Inje University, 197, Inje-Ro, Gimhae, Gyeongnam, 50834, Republic of Korea
| | - Yeon-Jeong Kim
- Laboratory of Microbiology and Immunology, College of Pharmacy, Inje University, 197, Inje-Ro, Gimhae, Gyeongnam, 50834, Republic of Korea.
- Inje Institute of Pharmaceutical Science and Research, Inje University, Gimhae, Gyeongnam, Republic of Korea.
- Smart Marine Therapeutic Center, Inje University, Gimhae, Gyeongnam, Republic of Korea.
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Qin L, Wang J, Cheng F, Cheng J, Zhang H, Zheng H, Liu Y, Liang Z, Wang B, Li C, Wang H, Ju Y, Tian H, Meng S. GPC3 and PEG10 peptides associated with placental gp96 elicit specific T cell immunity against hepatocellular carcinoma. Cancer Immunol Immunother 2023; 72:4337-4354. [PMID: 37932427 PMCID: PMC10700408 DOI: 10.1007/s00262-023-03569-2] [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: 06/10/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023]
Abstract
The placenta and tumors can exhibit a shared expression profile of proto-oncogenes. The basis of placenta-derived heat shock protein gp96, which induces prophylactic and therapeutic T cell responses against cancer including hepatocellular carcinoma (HCC), remains unknown. Here, we identified the associated long peptides from human placental gp96 using matrix-assisted laser desorption/ionization-time-of-flight and mass spectrometry and analyzed the achieved proteins through disease enrichment analysis. We found that placental gp96 binds to numerous peptides derived from 73 proteins that could be enriched in multiple cancer types. Epitope-harboring peptides from glypican 3 (GPC3) and paternally expressed gene 10 (PEG10) were the major antigens mediating anti-HCC T cell immunity. Molecular docking analysis showed that the GPC3- and PEG10-derived peptides, mainly obtained from the cytotrophoblast layer of the mature placenta, bind to the lumenal channel and client-bound domain of the gp96 dimer. Immunization with bone marrow-derived dendritic cells pulsed with recombinant gp96-GPC3 or recombinant gp96-PEG10 peptide complex induced specific T cell responses, and T cell transfusion led to pronounced growth inhibition of HCC tumors in nude mice. We demonstrated that the chaperone gp96 can capture antigenic peptides as an efficient approach for defining tumor rejection oncoantigens in the placenta and provide a basis for developing GPC3 and PEG10 peptide-based vaccines against HCC. This study provides insight into the underlying mechanism of the antitumor response mediated by embryonic antigens from fetal tissues, and this will incite more studies to identify potential tumor rejection antigens from placenta.
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Affiliation(s)
- Lijuan Qin
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiuru Wang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Fang Cheng
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiamin Cheng
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Han Zhang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Huaguo Zheng
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yongai Liu
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhentao Liang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Baifeng Wang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Changfei Li
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Haoyu Wang
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ying Ju
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
| | | | - Songdong Meng
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Ma J, Zhang G, Ye Y, Shang L, Hong S, Ma Q, Zhao Y, Gu C. Genome-Wide Identification and Expression Analysis of HSF Transcription Factors in Alfalfa ( Medicago sativa) under Abiotic Stress. PLANTS (BASEL, SWITZERLAND) 2022; 11:2763. [PMID: 36297789 PMCID: PMC9609925 DOI: 10.3390/plants11202763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/13/2022] [Accepted: 10/17/2022] [Indexed: 06/16/2023]
Abstract
Alfalfa (Medicago sativa) is one of the most important legume forage species in the world. It is often affected by several abiotic stressors that result in reduced yields and poor growth. Therefore, it is crucial to study the resistance of M. sativa to abiotic stresses. Heat shock transcription factors (HSF) are key players in a number of transcriptional regulatory pathways. These pathways play an essential role in controlling how plants react to different abiotic stressors. Studies on the HSF gene family have been reported in many species but have not yet undergone a thorough analysis in M. sativa. Therefore, in order to identify a more comprehensive set of HSF genes, from the genomic data, we identified 16 members of the MsHSF gene, which were unevenly distributed over six chromosomes. We also looked at their gene architectures and protein motifs, and phylogenetic analysis allowed us to divide them into 3 groups with a total of 15 subgroups. Along with these aspects, we then examined the physicochemical properties, subcellular localization, synteny analysis, GO annotation and enrichment, and protein interaction networks of amino acids. Finally, the analysis of 16 MsHSF genes' expression levels across all tissues and under four abiotic stresses using publicly available RNA-Seq data revealed that these genes had significant tissue-specific expression. Moreover, the expression of most MsHSF genes increased dramatically under abiotic stress, further validating the critical function played by the MsHSF gene family in abiotic stress. These results provided basic information about MsHSF gene family and laid a foundation for further study on the biological role of MsHSF gene in response to stress in M. sativa.
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Affiliation(s)
- Jin Ma
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Guozhe Zhang
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Yacheng Ye
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Linxue Shang
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Sidan Hong
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Qingqing Ma
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Yu Zhao
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
| | - Cuihua Gu
- College of Landscape and Architecture, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Zhejiang Provincial Key Laboratory of Germplasm Innovation and Utilization for Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
- Key Laboratory of National Forestry and Grassland Administration on Germplasm Innovation and Utilization for Southern Garden Plants, Zhejiang Agriculture & Forestry University, Hangzhou 311300, China
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6
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Hoang TX, Kim JY. Cell Surface Hsp90- and αMβ2 Integrin-Mediated Uptake of Bacterial Flagellins to Activate Inflammasomes by Human Macrophages. Cells 2022; 11:cells11182878. [PMID: 36139453 PMCID: PMC9496951 DOI: 10.3390/cells11182878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/11/2022] [Accepted: 09/12/2022] [Indexed: 11/16/2022] Open
Abstract
All-trans retinoic acid (ATRA) is an active metabolite of vitamin A, which plays an important role in the immune function. Here, we demonstrated that ATRA induces the heat shock protein (Hsp) 90 complex on the surface of THP-1 macrophages, which facilitates the internalization of exogenous bacterial flagellins to activate the inflammasome response. Mass spectrometric protein identification and co-immunoprecipitation revealed that the Hsp90 homodimer interacts with both Hsp70 and αMβ2 integrin. ATRA-induced complex formation was dependent on the retinoic acid receptor (RAR)/retinoid X receptor (RXR) pathway and intracellular calcium level and was essential for triggering the internalization of bacterial flagellin, which was clathrin dependent. Notably, in this process, αMβ2 integrin was found to act as a carrier to deliver flagellin to the cytosol to activate the inflammasome, leading to caspase-1 activity and secretion of interleukin (IL)-1β. Our study provides new insights into the underlying molecular mechanism by which exogenous bacterial flagellins are delivered into host cells without a bacterial transport system, as well as the mechanism by which vitamin A contributes to enhancing the human macrophage function to detect and respond to bacterial infection.
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Gao Z, Yao L, Pan L. Gene expression and functional analysis of different heat shock protein (HSPs) in Ruditapes philippinarum under BaP stress. Comp Biochem Physiol C Toxicol Pharmacol 2022; 251:109194. [PMID: 34619354 DOI: 10.1016/j.cbpc.2021.109194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/02/2021] [Accepted: 09/19/2021] [Indexed: 12/21/2022]
Abstract
Heat shock proteins (HSPs) are a class of highly conserved proteins which can protect cells against various types of stress. However, little information on the mechanism involved in the organic contaminants stress response of HSPs is available, especially in marine invertebrates. The present study was conducted to evaluate the responses of HSPs in clams (Ruditapes philippinarum) under Benzo[a] pyrene (BaP) exposure. The clams were exposed to BaP (concentrations: 0, 0.1, 1, 10 μg/L) for 15 days. 6 HSPs mRNA were classified, and the results of tissue distribution indicated that 4 HSPs gene expressed most in the digestive glands. The transcription level of 6 HSPs (HSP22-1, HSP22-2, HSP40A, HSP60, HSP70, HSP90) genes and the aryl hydrocarbon receptor signaling pathway-related genes, and detoxification system-related enzymes activities were analyzed at 0, 1, 3, 6, 10 and 15 days. The activities of phase II detoxification metabolic enzymes and signaling pathway related genes in clams were severely affected by BaP stress and presented significant difference. Our result suggested that HSPs were produced in the presence of BaP and participated in the process of detoxification metabolism to a certain extent. Additionally, the transcription of HSP40A gene may be used as a potential biomarker of BaP exposure due to its evident concentration- and time-dependent expression pattern. Overall, the study investigated the classification of HSPs in R. philippinarum, provided information about the expression profiles of various HSPs after BaP exposure and broadened the understanding mechanism of HSPs in detoxification defense system under PAHs stress in mollusks.
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Affiliation(s)
- Zhongyuan Gao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Linlin Yao
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China
| | - Luqing Pan
- The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, Qingdao, 266003, PR China.
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8
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Hsp70-containing extracellular vesicles are capable of activating of adaptive immunity in models of mouse melanoma and colon carcinoma. Sci Rep 2021; 11:21314. [PMID: 34716378 PMCID: PMC8556270 DOI: 10.1038/s41598-021-00734-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/15/2021] [Indexed: 12/21/2022] Open
Abstract
The release of Hsp70 chaperone from tumor cells is found to trigger the full-scale anti-cancer immune response. Such release and the proper immune reaction can be induced by the delivery of recombinant Hsp70 to a tumor and we sought to explore how the endogenous Hsp70 can be transported to extracellular space leading to the burst of anti-cancer activity. Hsp70 transport mechanisms were studied by analyzing its intracellular tracks with Rab proteins as well as by using specific inhibitors of membrane domains. To study Hsp70 forms released from cells we employed the assay consisting of two affinity chromatography methods. Hsp70 content in culture medium and extracellular vesicles (EVs) was measured with the aid of ELISA. The properties and composition of EVs were assessed using nanoparticle tracking analysis and immunoblotting. The activity of immune cells was studied using an assay of cytotoxic lymphocytes, and for in vivo studies we employed methods of affinity separation of lymphocyte fractions. Analyzing B16 melanoma cells treated with recombinant Hsp70 we found that the chaperone triggered extracellular transport of its endogenous analog in soluble and enclosed in EVs forms; both species efficiently penetrated adjacent cells and this secondary transport was corroborated with the strong increase of Natural Killer (NK) cell toxicity towards melanoma. When B16 and CT-26 colon cancer cells before their injection in animals were treated with Hsp70-enriched EVs, a powerful anti-cancer effect was observed as shown by a two-fold reduction in tumor growth rate and elevation of life span. We found that the immunomodulatory effect was due to the enhancement of the CD8-positive response and anti-tumor cytokine accumulation; supporting this there was no delay in CT-26 tumor growth when Hsp70-enriched EVs were grafted in nude mice. Importantly, pre-treatment of B16 cells with Hsp70-bearing EVs resulted in a decline of arginase-1-positive macrophages, showing no generation of tumor-associated macrophages. In conclusion, Hsp70-containing EVs generated by specifically treated cancer cells give a full-scale and effective pattern of anti-tumor immune responses.
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Albakova Z, Mangasarova Y, Sapozhnikov A. Heat Shock Proteins in Lymphoma Immunotherapy. Front Immunol 2021; 12:660085. [PMID: 33815422 PMCID: PMC8012763 DOI: 10.3389/fimmu.2021.660085] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 02/26/2021] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy harnessing the host immune system for tumor destruction revolutionized oncology research and advanced treatment strategies for lymphoma patients. Lymphoma is a heterogeneous group of cancer, where the central roles in pathogenesis play immune evasion and dysregulation of multiple signaling pathways. Immunotherapy-based approaches such as engineered T cells (CAR T), immune checkpoint modulators and NK cell-based therapies are now in the frontline of lymphoma research. Even though emerging immunotherapies showed promising results in treating lymphoma patients, low efficacy and on-target/off-tumor toxicity are of a major concern. To address that issue it is suggested to look into the emerging role of heat shock proteins. Heat shock proteins (HSPs) showed to be highly expressed in lymphoma cells. HSPs are known for their abilities to modulate immune responses and inhibit apoptosis, which made their successful entry into cancer clinical trials. Here, we explore the role of HSPs in Hodgkin and Non-Hodgkin lymphoma and their involvement in CAR T therapy, checkpoint blockade and NK cell- based therapies. Understanding the role of HSPs in lymphoma pathogenesis and the ways how HSPs may enhance anti-tumor responses, may help in the development of more effective, specific and safe immunotherapy.
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Affiliation(s)
- Zarema Albakova
- Department of Biology, Lomonosov Moscow State University, Moscow, Russia
- Department of Immunology, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | | | - Alexander Sapozhnikov
- Department of Biology, Lomonosov Moscow State University, Moscow, Russia
- Department of Immunology, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
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10
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Khan M, Zhao Z, Arooj S, Fu Y, Liao G. Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy. Front Immunol 2020; 11:587460. [PMID: 33329567 PMCID: PMC7710690 DOI: 10.3389/fimmu.2020.587460] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022] Open
Abstract
Programmed death protein 1 (PD-1) interaction with PD-L1 deliver immunosuppressive environment for tumor growth, and its blockade with directed monoclonal antibodies (anti-PD-1/anti-PD-L1) has shown remarkable clinical outcome. Lately, their soluble counterparts, sPD-1 and sPD-L1, have been detected in plasma, and elevated levels have been associated with advanced disease, clinical stages, and worst prognosis for cancer patients. Elevated plasma levels of sPD-L1 have been correlated with worst prognosis in several studies and has displayed a persistent outlook. On the other hand, sPD-1 levels have been inconsistent in their predictive and prognostic ability. Pretherapeutic higher sPD-1 plasma levels have shown to predict advanced disease state and to a lesser extent worst prognosis. Any increase in sPD-1 plasma level post therapeutically have been correlated with improved survival for various cancers. In vitro and in vivo studies have shown sPD-1 ability to bind PD-L1 and PD-L2 and block PD-1/PD-L1 interaction. Local delivery of sPD-1 in cancer tumor microenvironment through local gene therapy have demonstrated an increase in tumor specific CD8+ T cell immunity and tumor growth reduction. It had also exhibited enhancement of T cell immunity induced by vaccination and other gene therapeutic agents. Furthermore, it may also lessen the inhibitory effect of circulating sPD-L1 and enhance the effects of mAb-based immunotherapy. In this review, we highlight various aspects of sPD-1 role in cancer prediction, prognosis, and anti-cancer immunity, as well as, its therapeutic value for local gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoint interactions.
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Affiliation(s)
- Muhammad Khan
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.,Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhihong Zhao
- Department of Nephrology, Shenzhen People's Hospital, Second Clinical Medicine Centre, Jinan University, Shenzhen, China
| | - Sumbal Arooj
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.,Department of Biochemistry, University of Sialkot, Sialkot, Pakistan
| | - Yuxiang Fu
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Guixiang Liao
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
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11
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Liu R, Su Z, Zhou H, Huang Q, Fan S, Liu C, Han Y. LsHSP70 is induced by high temperature to interact with calmodulin, leading to higher bolting resistance in lettuce. Sci Rep 2020; 10:15155. [PMID: 32939023 PMCID: PMC7495476 DOI: 10.1038/s41598-020-72443-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 08/28/2020] [Indexed: 11/10/2022] Open
Abstract
High temperatures have significant impacts on heat-tolerant bolting in lettuce. In this study, it was found that high temperatures could facilitate the accumulation of GA in lettuce to induce bolting, with higher expression levels of two heat shock protein genes LsHsp70-3701 and LsHsp70-2711. By applying VIGS technology, these two Hsp70 genes were incompletely silenced and plant morphological changes under heat treatment of silenced plants were observed. The results showed that lower expression levels of these two genes could enhance bolting stem length of lettuce under high temperatures, which means these two proteins may play a significant role in heat-induced bolting tolerance. By using the yeast two-hybrid technique, it was found that a calmodulin protein could interact with LsHsp70 proteins in a high-temperature stress cDNA library, which was constructed for lettuce. Also, the Hsp70-calmodulin combination can be obtained at high temperatures. According to these results, it can be speculated that the interaction between Hsp70 and calmodulin could be induced under high temperatures and higher GA contents can be obtained at the same time. This study analyses the regulation of heat tolerance in lettuce and lays a foundation for additional studies of heat resistance in lettuce.
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Affiliation(s)
- Ran Liu
- Beijing Key Laboratory of New Technology in Agricultural Application, National Demonstration Center for Experimental Plant Production Education, Beijing University of Agriculture, Beijing, 102206, China
| | - Zhenqi Su
- Beijing Key Laboratory of New Technology in Agricultural Application, National Demonstration Center for Experimental Plant Production Education, Beijing University of Agriculture, Beijing, 102206, China
| | - Huiyan Zhou
- Laboratory of Cell & Molecular Biology, Institute of Vegetable Science, Zhejiang University, Hangzhou, 310058, China
| | - Qian Huang
- Beijing Key Laboratory of New Technology in Agricultural Application, National Demonstration Center for Experimental Plant Production Education, Beijing University of Agriculture, Beijing, 102206, China
| | - Shuangxi Fan
- Beijing Key Laboratory of New Technology in Agricultural Application, National Demonstration Center for Experimental Plant Production Education, Beijing University of Agriculture, Beijing, 102206, China
| | - Chaojie Liu
- Beijing Key Laboratory of New Technology in Agricultural Application, National Demonstration Center for Experimental Plant Production Education, Beijing University of Agriculture, Beijing, 102206, China
| | - Yingyan Han
- Beijing Key Laboratory of New Technology in Agricultural Application, National Demonstration Center for Experimental Plant Production Education, Beijing University of Agriculture, Beijing, 102206, China.
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12
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Quan J, Kang Y, Luo Z, Zhao G, Ma F, Li L, Liu Z. Identification and characterization of long noncoding RNAs provide insight into the regulation of gene expression in response to heat stress in rainbow trout (Oncorhynchus mykiss). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2020; 36:100707. [PMID: 32693384 DOI: 10.1016/j.cbd.2020.100707] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 06/07/2020] [Accepted: 06/26/2020] [Indexed: 12/22/2022]
Abstract
Rainbow trout are typical cold-water fish species. However, with the intensification of global warming, high temperatures have severely restricted the development of aquaculture during the summer. Understanding the molecular regulatory mechanisms of rainbow trout responses to heat stress will be beneficial for alleviating heat stress-related damage. In this study, we performed RNA-seq of liver tissues from rainbow trout under heat stress (24 °C) and control conditions (18 °C) to identify lncRNAs and target genes by strand-specific library. Changes in nonspecific immune parameters revealed that a strong stress response occurred in rainbow trout at 24 °C. More than 658 million filtered reads and 5916 lncRNAs were identified from six libraries. A total of 927 novel lncRNAs were identified, and 428 differentially expressed lncRNAs were screened with stringent thresholds. The RNA-seq results were verified by RT-qPCR. In addition, a regulatory network of lncRNA-mRNA functional interactions was constructed, and the potential antisense, cis and trans targets of lncRNAs were predicted. GO and KEGG enrichment analyses showed that many target genes involved in maintenance of homeostasis or adaptation to stress and stimuli were highly induced under heat stress. Several regulatory pathways were also found to be involved in heat stress, including the thyroid hormone signaling pathway, the PI3K-Akt signaling pathway, and the estrogen signaling pathway, among others. These results broaden our understanding of lncRNAs associated with heat stress and provide new insights into the lncRNA mediated regulation of the rainbow trout heat stress response.
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Affiliation(s)
- Jinqiang Quan
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China
| | - Yujun Kang
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China
| | - Zhicheng Luo
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China
| | - Guiyan Zhao
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China
| | - Fang Ma
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China; College of Bioengineering and Technology, Tianshui Normal University, Tianshui 741000, PR China
| | - Lanlan Li
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China
| | - Zhe Liu
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, PR China.
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13
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Lee MJ, Jo H, Park SH, Ko MK, Kim SM, Kim B, Park JH. Advanced Foot-And-Mouth Disease Vaccine Platform for Stimulation of Simultaneous Cellular and Humoral Immune Responses. Vaccines (Basel) 2020; 8:E254. [PMID: 32481687 PMCID: PMC7349985 DOI: 10.3390/vaccines8020254] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/16/2020] [Accepted: 05/25/2020] [Indexed: 12/16/2022] Open
Abstract
Currently available commercial foot-and-mouth disease (FMD) vaccines have various limitations, such as the slow induction and short-term maintenance of antibody titers. Therefore, a novel FMD vaccine that can rapidly induce high neutralizing antibody titers to protect the host in early stages of an FMD virus infection, maintain high antibody titers for long periods after one vaccination dose, and confer full protection against clinical symptoms by simultaneously stimulating cellular and humoral immunity is needed. Here, we developed immunopotent FMD vaccine strains A-3A and A-HSP70, which elicit strong initial cellular immune response and induce humoral immune response, including long-lasting memory response. We purified the antigen (inactivated virus) derived from these immunopotent vaccine strains, and evaluated the immunogenicity and efficacy of the vaccines containing these antigens in mice and pigs. The immunopotent vaccine strains A-3A and A-HSP70 demonstrated superior immunogenicity compared with the A strain (backbone strain) in mice. The oil emulsion-free vaccine containing A-3A and A-HSP70 antigens effectively induced early, mid-term, and long-term immunity in mice and pigs by eliciting robust cellular and humoral immune responses through the activation of co-stimulatory molecules and the secretion of proinflammatory cytokines. We successfully derived an innovative FMD vaccine formulation to create more effective FMD vaccines.
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Affiliation(s)
- Min Ja Lee
- Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do 39660, Korea; (H.J.); (S.H.P.); (M.-K.K.); (S.-M.K.); (B.K.)
| | | | | | | | | | | | - Jong-Hyeon Park
- Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do 39660, Korea; (H.J.); (S.H.P.); (M.-K.K.); (S.-M.K.); (B.K.)
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14
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Treatment of Yersinia similis with the cationic lipid DOTAP enhances adhesion to and invasion into intestinal epithelial cells - A proof-of-principle study. Biochem Biophys Res Commun 2020; 525:378-383. [PMID: 32098674 DOI: 10.1016/j.bbrc.2020.02.081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 02/11/2020] [Indexed: 11/21/2022]
Abstract
The monocationic quaternary surfactant DOTAP has been used for the delivery of nucleic acids and peptides into mammalian cells. This study tested the applicability of DOTAP for the enhancement of adhesion and invasion frequencies of Yersinia (Y.) similis to enable the analysis of the effects of low-pathogenic bacteria on intestinal epithelial cells. Incubation of Y. similis with DOTAP ahead of infection of C2BBe1 intestinal epithelial cells increased invasion and adhesion frequency four- and five-fold, respectively, in plating assays. Proteomic approaches confirmed the increased bacterial load on infected cells: analysis of protein extracts by two-dimensional difference gel electrophoresis (2D-DIGE) revealed higher amounts of bacterial proteins present in the cells infected with DOTAP-treated bacteria. MALDI-TOF mass spectrometry of selected spots from gel-separated protein extracts confirmed the presence of both bacterial and human cell proteins in the samples. Label-free quantitative proteomics analysis identified 1170 human cell proteins and 699 bacterial proteins. Three times more bacterial proteins (279 vs. 93) were detected in C2BBe1 cells infected with DOTAP-treated bacteria compared to infections with untreated bacteria. Infections with DOTAP-treated Y. similis led to a significant upregulation of the stress-inducible ubiquitin-conjugating enzyme UBE2M in C2BBe1 cells. This points towards a stronger impact of the stress and infection responsive transcription factor AP-1 by enhanced bacterial load. DOTAP-treatment of uninfected C2BBe1 cells led to a significant downregulation of the transmembrane trafficking protein TMED10. The application of DOTAP could be helpful for investigating the impact of otherwise low adherent or invasive bacteria on cultivated mammalian cells without utilisation of genetic modifications.
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15
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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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16
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Skalina KA, Singh S, Chavez CG, Macian F, Guha C. Low Intensity Focused Ultrasound (LOFU)-mediated Acoustic Immune Priming and Ablative Radiation Therapy for in situ Tumor Vaccines. Sci Rep 2019; 9:15516. [PMID: 31664044 PMCID: PMC6820551 DOI: 10.1038/s41598-019-51332-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 09/17/2019] [Indexed: 12/31/2022] Open
Abstract
Focal ablative therapies have been primarily used for local tumor ablation. However, they often fail to impact systemic disease. Here we propose the use of low intensity focused ultrasound (LOFU), a noninvasive, nontoxic, conformal therapy, to deliver acoustic stress to the tumor for immune priming. We demonstrate that LOFU significantly induces expression and cell surface localization of heat shock proteins in murine breast (4T1) and prostate adenocarcinoma (TPSA23) cancer cell lines. In vivo LOFU followed by ablative radiation therapy (RT) results in primary tumor cure, upregulation of a cytotoxic immune response and induction of immunological memory by inhibiting secondary tumor growth upon re-challenge with tumor cells. We, therefore, describe a regimen of a combination therapy with noninvasive, acoustic immune priming and ablative radiation therapy to generate an in situ tumor vaccine, induce CD8+ T cells against tumor-associated antigens and provide a viable oncologic treatment option for solid tumors.
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Affiliation(s)
- Karin A Skalina
- Departments of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Saurabh Singh
- Radiation Oncology, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, NY, USA.,Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Claudia Gutierrez Chavez
- Radiation Oncology, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, NY, USA.,Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Fernando Macian
- Departments of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Chandan Guha
- Departments of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. .,Urology, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, NY, USA. .,Radiation Oncology, Albert Einstein College of Medicine & Montefiore Medical Center, Bronx, NY, USA. .,Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY, USA.
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17
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Transcriptome Analysis Shows That IFN-I Treatment and Concurrent SAV3 Infection Enriches MHC-I Antigen Processing and Presentation Pathways in Atlantic Salmon-Derived Macrophage/Dendritic Cells. Viruses 2019; 11:v11050464. [PMID: 31121853 PMCID: PMC6563251 DOI: 10.3390/v11050464] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/16/2019] [Accepted: 05/17/2019] [Indexed: 01/17/2023] Open
Abstract
Type I interferons (IFNs) have been shown to play an important role in shaping adaptive immune responses in addition to their antiviral properties in immune cells. To gain insight into the impact of IFN-I-induced pathways involved in early adaptive immune responses, i.e., antigen-presenting pathways, in an Atlantic salmon-derived (Salmo salar L.) macrophage cell line (TO-cells), we used a comparative de novo transcriptome analysis where cells were treated with IFN-I or kept untreated and concurrently infected with salmonid alphavirus subtype 3 (SAV3). We found that concurrent treatment of TO-cells with IFN-I and SAV3 infection (SAV3/IFN+) significantly enriched the major histocompatibility complex class I (MHC-I) pathway unlike the non-IFN-I treated TO-cells (SAV3/IFN−) that had lower expression levels of MHC-I pathway-related genes. Genes such as the proteasomal activator (PA28) and β-2 microglobulin (β2M) were only differentially expressed in the SAV3/IFN+ cells and not in the SAV3/IFN− cells. MHC-I pathway genes like heat shock protein 90 (Hsp90), transporter of antigen associated proteins (TAPs) and tapasin had higher expression levels in the SAV3/IFN+ cells than in the SAV3/IFN− cells. There were no MHC-II pathway-related genes upregulated in SAV3/IFN+-treated cells, and cathepsin S linked to the degradation of endosomal antigens in the MHC-II pathway was downregulated in the SAV3/IFN− cells. Overall, our findings show that concurrent IFN-I treatment of TO-cells and SAV3 infection enriched gene expression linked to the MHC-I antigen presentation pathway. Data presented indicate a role of type I IFNs in strengthening antigen processing and presentation that may facilitate activation particularly of CD8+ T-cell responses following SAV3 infection, while SAV3 infection alone downplayed MHC-II pathways.
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18
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19
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Shevtsov M, Huile G, Multhoff G. Membrane heat shock protein 70: a theranostic target for cancer therapy. Philos Trans R Soc Lond B Biol Sci 2018; 373:rstb.2016.0526. [PMID: 29203711 PMCID: PMC5717526 DOI: 10.1098/rstb.2016.0526] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2017] [Indexed: 12/19/2022] Open
Abstract
Members of the 70 kDa stress protein family are found in nearly all subcellular compartments of nucleated cells where they fulfil a number of chaperoning functions. Heat shock protein 70 (HSP70), also termed HSPA1A, the major stress-inducible member of this family is overexpressed in a large variety of different tumour types. Apart from its intracellular localization, a tumour-selective HSP70 membrane expression has been determined. A membrane HSP70–positive tumour phenotype is associated with aggressiveness and therapy resistance, but also serves as a recognition structure for targeted therapies. Furthermore, membrane-bound and extracellularly residing HSP70 derived from tumour cells play pivotal roles in eliciting anti-tumour immune responses. Herein, we want to shed light on the multiplicity of different activities of HSP70, depending on its intracellular, membrane and extracellular localization with the goal to use membrane HSP70 as a target for novel therapies including nanoparticle-based approaches for the treatment of cancer. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
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Affiliation(s)
- Maxim Shevtsov
- Klinikum rechts der Isar, Department of Radiation Oncology, Technische Universität München, Ismaninger Strasse 22, Munich 81675, Germany.,Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Avenue, 4, St Petersburg 194064, Russia
| | - Gao Huile
- West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Gabriele Multhoff
- Klinikum rechts der Isar, Department of Radiation Oncology, Technische Universität München, Ismaninger Strasse 22, Munich 81675, Germany
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20
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Rodriguez-Iturbe B, Lanaspa MA, Johnson RJ. The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension. Br J Pharmacol 2018; 176:1829-1838. [PMID: 29679484 DOI: 10.1111/bph.14334] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/26/2018] [Accepted: 03/28/2018] [Indexed: 12/24/2022] Open
Abstract
Autoimmunity is increasingly recognized as having a central role in essential hypertension. Heat shock proteins (HSPs) are immunodominant molecules with high interspecies homology and autoimmune reactivity directed against HSP70 may play a role in the pathogenesis of hypertension. Autoimmunity to HSP70 may result from molecular mimicry between human HSP and bacterial HSP or, alternatively, as a response to HSP70-peptide complexes generated during cellular stress and delivered to the major histocompatibility complex by antigen-presenting cells. HSP70 is increased in the circulation and kidney of hypertensive patients, and genetic polymorphisms of HSP70 are associated with essential hypertension. Depending on the route and conditions of administration, HSP70 may induce or suppress immune-related inflammation. Renal inflammation induced by immunity to HSP70 causes hypertension in laboratory animals, and administration of specific peptide sequences of HSP70 results in a protective anti-inflammatory response that prevents and corrects salt-induced hypertension. Potential therapeutic uses of HSP70 in essential hypertension deserve to be investigated. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
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Affiliation(s)
- Bernardo Rodriguez-Iturbe
- Nephrology Service Hospital Universitario, Universidad del Zulia, Instituto Venezolano de Investigaciones Científicas (IVIC-Zulia), Maracaibo, Venezuela
| | - Miguel A Lanaspa
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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21
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New insights to structure and immunological features of Leishmania lipophosphoglycan3. Biomed Pharmacother 2017; 95:1369-1374. [PMID: 28946184 DOI: 10.1016/j.biopha.2017.09.061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 09/01/2017] [Accepted: 09/13/2017] [Indexed: 12/24/2022] Open
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22
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Abstract
Heat shock protein 70, (Hsp70) constitutes a powerful system of cytoprotection in all organisms studied to date. Exerting such activity, Hsp70 rescues cancer cells from antitumor therapy, posing a great challenge for oncologists. In contrast to its protective action, Hsp70 was found to be released from cancer cells, prompting cytotoxic lymphocytes to target and kill the tumor. A great number of vaccines have been developed on the basis of the ability of Hsp70 to present tumor antigen or to elevate the sensitivity of cancer cells to cytotoxic lymphocytes. In this commentary, we consider novel data on the employment of pure Hsp70 in the therapy of glioma and melanoma malignancies. We show that intratumorally delivered Hsp70 penetrates cancer cells and pulls its intracellular analog outside of the cell. This displacement may activate cells, constituting both innate and adaptive immunity. In vivo delivery of Hsp70 was found to inhibit tumor growth and to extend survival. The technology of intratumoral injection of pure Hsp70 passed through preclinical trials and was investigated in clinics for children with brain cancer; the results show the safety and feasibility of a new approach.
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Affiliation(s)
- Irina V Guzhova
- a Institute of Cytology of Russian Academy of Sciences , St. Petersburg , Russia
| | - Boris A Margulis
- a Institute of Cytology of Russian Academy of Sciences , St. Petersburg , Russia
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23
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Zhu J, Zhang Y, Zhang A, He K, Liu P, Xu LX. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation. Sci Rep 2016; 6:27136. [PMID: 27256519 PMCID: PMC4891716 DOI: 10.1038/srep27136] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 05/05/2016] [Indexed: 12/11/2022] Open
Abstract
Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.
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Affiliation(s)
- Jun Zhu
- The School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.,Neurosurgery Department, Ruijin Hospital,School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Zhang
- The School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Aili Zhang
- The School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Kun He
- The School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Ping Liu
- The School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Lisa X Xu
- The School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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24
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Xiong Y, Dong S, Zhao X, Guo KJ, Gasco L, Zoccarato I. Gene expressions and metabolomic research on the effects of polyphenols from the involucres of Castanea mollissima Blume on heat-stressed broilers chicks. Poult Sci 2016; 95:1869-80. [PMID: 27209434 DOI: 10.3382/ps/pew170] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2016] [Indexed: 02/05/2023] Open
Abstract
To study the effects of polyphenolic extract from involucres of Castanea mollissima Blume ( PICB: ), a novel approach using gene expression by real time polymerase chain reaction ( REAL-TIME PCR: ) coupled with metabolomic profiling technique was established to explain the mechanism of PICB on heat-stressed broiler chicks. Four thousand 28-day-old male Arbor Acres (AA) broilers were randomly assigned to 5 groups (4 replicates / group, 20 chicks / replicate), in which group 1 was normal control group fed with basic ration; groups 2, 3, 4, and 5 were fed with the basic ration with a supplementation of 0.2% Vitamin C ( VC: ), or 0.2%, 0.3%, or 0.4% of PICB respectively. After 1 wk of adaptation, heat stress was applied for 7 consecutive days. On d 3 and d 7 of heat stress, the chicks were sacrificed and sampled. The mRNA expression of heat stress protein 70 (HSP70), glutathione peroxidase ( GSH-PX: ), ornithine decarboxylase ( ODC: ), epidermal growth factor ( EGF: ) and epidermal growth factor receptor ( EGFR: ) were detected by real-time PCR using samples from jejunum mucosa. The serum and jejunum mucosa metabolomic profiles of PICB group showing best antioxidative effects and control group at d 3 were studied using the method of the gas chromatography - time of flight mass spectrometry ( GT-TOF-MS: ), followed by principal component analysis and partial least squares-discriminate analysis. Potential biomarkers were found using Student's t-test. The results showed mRNA expressions of HSP70, GSH-Px, ODC, EGF, and EGFR were altered by the supplementation of PICB. PICB exhibited antioxidative and growth promoting effects, and 0.3% PICB supplementation level exhibited the best. Three metabolites in the serum and 5 in the jejunum mucosa were identified as potential biomarkers. They were considered to be in accordance with antioxidative and growth promoting effects of PICB, which involved in the energy metabolism (sorbitol, palmitic acid), carbohydrate metabolism, amino acids metabolism (serine, L-ornithine), glutathione metabolism (glutamate, L-ornithine), GnRH signaling pathway (inositol), etc. These findings provided novel insights into our understanding of molecular mechanism of PICB effects on heat-stressed chicks.
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Affiliation(s)
- Y Xiong
- College of Animal Science and Technology, Beijing University of Agriculture, No. 7 Beinong Road, Changping District, Beijing 102206, P.R. China
| | - S Dong
- College of Animal Science and Technology, Beijing University of Agriculture, No. 7 Beinong Road, Changping District, Beijing 102206, P.R. China
| | - X Zhao
- College of Animal Science and Technology, Beijing University of Agriculture, No. 7 Beinong Road, Changping District, Beijing 102206, P.R. China
| | - K J Guo
- College of Animal Science and Technology, Beijing University of Agriculture, No. 7 Beinong Road, Changping District, Beijing 102206, P.R. China
| | - Laura Gasco
- Department of Agricultural, Forest, and Food Sciences, Turin University. Grugliasco (TO), Italy
| | - Ivo Zoccarato
- Department of Agricultural, Forest, and Food Sciences, Turin University. Grugliasco (TO), Italy
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Duan XH, Li TF, Zhou GF, Han XW, Zheng CS, Chen PF, Feng GS. Transcatheter arterial embolization combined with radiofrequency ablation activates CD8(+) T-cell infiltration surrounding residual tumors in the rabbit VX2 liver tumors. Onco Targets Ther 2016; 9:2835-44. [PMID: 27274279 PMCID: PMC4876106 DOI: 10.2147/ott.s95973] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Purpose To evaluate the effect of transcatheter arterial embolization (TAE) combined with radiofrequency ablation (RFA) treatment (TAE + RFA) on the expression of heat shock protein 70 (HSP70) in residual tumors and explore the relationship between the HSP70 and CD8+ T-cell infiltrate surrounding residual tumors in the rabbit VX2 liver tumor model. Materials and methods Animals with VX2 liver tumors were randomized into four groups (control, TAE, RFA, and TAE + RFA) with 15 rabbits in each group. Five rabbits in each group were sacrificed on days 1, 3, and 7 after treatment. HSP70 expression and infiltration of CD8+ T-cells in the liver and residual tumors surrounding the necrosis zone were detected by immunohistochemistry staining. The maximal diameters of tumor necrosis, numbers of metastases, and tumor growth rate were compared on day 7 after treatment. Results TAE + RFA achieved larger maximal diameter of tumor necrosis, lower tumor growth rate, and fewer metastatic lesions, compared with other treatments on day 7. The number of CD8+ T-cells in the TAE + RFA group was significantly higher than in other groups on days 1, 3, and 7. There was a positive correlation between HSP70 expression level and infiltration of CD8+ T-cells surrounding the residual tumor on day 1 (r=0.9782, P=0.012), day 3 (r=0.93, P=0.021), and day 7 (r=0.8934, P=0.034). Conclusion In the rabbit VX2 liver tumor model, TAE + RFA activated the highest number of CD8+ T-cells surrounding residual tumors. TAE + RFA appears to be a beneficial therapeutic modality for tumor control and antitumor immune response in this model.
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Affiliation(s)
- Xu-Hua Duan
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Henan Province, Zhengzhou, People's Republic of China
| | - Teng-Fei Li
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Henan Province, Zhengzhou, People's Republic of China
| | - Guo-Feng Zhou
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xin-Wei Han
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Henan Province, Zhengzhou, People's Republic of China
| | - Chuan-Sheng Zheng
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Peng-Fei Chen
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Henan Province, Zhengzhou, People's Republic of China
| | - Gan-Sheng Feng
- Department of Interventional Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Kumar S, Stokes J, Singh UP, Scissum Gunn K, Acharya A, Manne U, Mishra M. Targeting Hsp70: A possible therapy for cancer. Cancer Lett 2016; 374:156-166. [PMID: 26898980 PMCID: PMC5553548 DOI: 10.1016/j.canlet.2016.01.056] [Citation(s) in RCA: 162] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 01/28/2016] [Accepted: 01/31/2016] [Indexed: 01/13/2023]
Abstract
In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.
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Affiliation(s)
- Sanjay Kumar
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA
| | - James Stokes
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA
| | - Udai P Singh
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Karyn Scissum Gunn
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA
| | - Arbind Acharya
- Centre of Advance Study in Zoology, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Manoj Mishra
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36101, USA.
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Park KT, Seo KS, Godwin NA, Van Wie BJ, Gulbahar MY, Park YH, Davis WC. Characterization and expression of monoclonal antibody-defined molecules on resting and activated bovine αβ, γδ T and NK cells. Vet Immunol Immunopathol 2015; 168:118-30. [PMID: 26384699 DOI: 10.1016/j.vetimm.2015.09.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 08/27/2015] [Accepted: 09/07/2015] [Indexed: 01/10/2023]
Abstract
Monoclonal antibodies (mAbs) specific for leukocyte differentiation molecules (LDMs) were developed during the past few decades to expand reagents for research in ruminants, pigs, and horses. The specificity of some of the mAb-defined molecules was determined through participation in international workshops. Other molecules identified with mAbs during this time, and more recently with mAbs developed after the workshops, have remained partially characterized. Efforts are now underway to characterize the specificity of these mAbs. As reported here, flow cytometry (FC) was used to screen two sets of hybridomas to determine how many of the hybridomas produce mAbs that detect molecules with up-regulated expression on activated lymphocytes or NK cells. Thirty four hybridomas were identified. Comparison of the patterns of reactivity of the mAbs showed some of the mAbs formed clusters that recognize 5 different molecules. FC showed one cluster recognized CD25. Use of mass spectrometry showed 4 clusters recognized orthologues of CD26, CD50, gp96 and signaling lymphocytic activation molecule family member 9 (SLAMF9). Verification and documentation that CD26, CD50, and SLAMF9 were only up-regulated on activated cells was obtained with PBMC from calves vaccinated with a Mycobacterium avium paratuberculosis mutant, Map-relA. CD26 and CD50 were up-regulated on NK cells, CD4 and CD8 T cells and γδ T cells. SLAMF9 was only up-regulated on CD4, CD8, and γδ T cells. gp96 was detected on granulocytes, monocytes and activated NK cells. Detection was attributable to the binding of gp96 to its receptor CD91.
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Affiliation(s)
- Kun Taek Park
- Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA
| | - Keun Seok Seo
- Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA
| | - Natasha A Godwin
- School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA, USA
| | - Bernard J Van Wie
- School of Chemical Engineering and Bioengineering, Washington State University, Pullman, WA, USA
| | - M Yavuz Gulbahar
- Department of Pathology, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Yong Ho Park
- Department of Veterinary Microbiology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - William C Davis
- Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA.
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Fucikova J, Moserova I, Urbanova L, Bezu L, Kepp O, Cremer I, Salek C, Strnad P, Kroemer G, Galluzzi L, Spisek R. Prognostic and Predictive Value of DAMPs and DAMP-Associated Processes in Cancer. Front Immunol 2015; 6:402. [PMID: 26300886 PMCID: PMC4528281 DOI: 10.3389/fimmu.2015.00402] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/22/2015] [Indexed: 01/04/2023] Open
Abstract
It is now clear that human neoplasms form, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system. In particular, accumulating evidence demonstrates that the efficacy of most, if not all, chemo- and radiotherapeutic agents commonly employed in the clinic critically depends on the (re)activation of tumor-targeting immune responses. One of the mechanisms whereby conventional chemotherapeutics, targeted anticancer agents, and radiotherapy can provoke a therapeutically relevant, adaptive immune response against malignant cells is commonly known as “immunogenic cell death.” Importantly, dying cancer cells are perceived as immunogenic only when they emit a set of immunostimulatory signals upon the activation of intracellular stress response pathways. The emission of these signals, which are generally referred to as “damage-associated molecular patterns” (DAMPs), may therefore predict whether patients will respond to chemotherapy or not, at least in some settings. Here, we review clinical data indicating that DAMPs and DAMP-associated stress responses might have prognostic or predictive value for cancer patients.
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Affiliation(s)
- Jitka Fucikova
- Sotio , Prague , Czech Republic ; Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague , Czech Republic
| | - Irena Moserova
- Sotio , Prague , Czech Republic ; Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague , Czech Republic
| | - Linda Urbanova
- Sotio , Prague , Czech Republic ; Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague , Czech Republic
| | - Lucillia Bezu
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris , France ; U1138, INSERM , Paris , France ; Sorbonne Paris Cité, Université Paris Descartes , Paris , France ; Université Pierre et Marie Curie , Paris , France ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute , Villejuif , France
| | - Oliver Kepp
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris , France ; U1138, INSERM , Paris , France ; Sorbonne Paris Cité, Université Paris Descartes , Paris , France ; Université Pierre et Marie Curie , Paris , France ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute , Villejuif , France
| | - Isabelle Cremer
- Sorbonne Paris Cité, Université Paris Descartes , Paris , France ; Université Pierre et Marie Curie , Paris , France ; Equipe 13, Centre de Recherche des Cordeliers , Paris , France
| | - Cyril Salek
- Institute of Hematology and Blood Transfusion , Prague , Czech Republic
| | - Pavel Strnad
- Department of Gynecology and Obsterics, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague , Czech Republic
| | - Guido Kroemer
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris , France ; U1138, INSERM , Paris , France ; Sorbonne Paris Cité, Université Paris Descartes , Paris , France ; Université Pierre et Marie Curie , Paris , France ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute , Villejuif , France ; Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP , Paris , France
| | - Lorenzo Galluzzi
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris , France ; U1138, INSERM , Paris , France ; Sorbonne Paris Cité, Université Paris Descartes , Paris , France ; Université Pierre et Marie Curie , Paris , France ; Gustave Roussy Comprehensive Cancer Institute , Villejuif , France
| | - Radek Spisek
- Sotio , Prague , Czech Republic ; Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague , Czech Republic
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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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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 2014; 57:311-25. [PMID: 24254084 DOI: 10.1007/s12026-013-8468-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [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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31
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Bai JF, Liu P, Xu LX. Recent Advances in Thermal Treatment Techniques and Thermally Induced Immune Responses Against Cancer. IEEE Trans Biomed Eng 2014; 61:1497-505. [DOI: 10.1109/tbme.2014.2314357] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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32
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Structural insights into complexes of glucose-regulated Protein94 (Grp94) with human immunoglobulin G. relevance for Grp94-IgG complexes that form in vivo in pathological conditions. PLoS One 2014; 9:e86198. [PMID: 24489700 PMCID: PMC3904872 DOI: 10.1371/journal.pone.0086198] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 12/04/2013] [Indexed: 01/17/2023] Open
Abstract
While the mechanism by which Grp94 displays its chaperone function with client peptides in the cell has been elucidated extensively, much less is known about the nature and properties of how Grp94 can engage binding to proteins once it is exposed on the cell surface or liberated in the extra-cellular milieu, as occurs in pathological conditions. In this work, we wanted to investigate the molecular aspects and structural characteristics of complexes that Grp94 forms with human IgG, posing the attention on the influence that glycosylation of Grp94 might have on the binding capacity to IgG, and on the identification of sites involved in the binding. To this aim, we employed both native, fully glycosylated and partially glycosylated Grp94, and recombinant, non-glycosylated Grp94, as well as IgG subunits, in different experimental conditions, including the physiological setting of human plasma. Regardless of the species and type, Grp94 engages a similar, highly specific and stable binding with IgG that involves sites located in the N-terminal domain of Grp94 and the hinge region of whole IgG. Grp94 does not form stable complex with Fab, F(ab)2 or Fc. Glycosylation turns out to be an obstacle to the Grp94 binding to IgG, although this negative effect can be counteracted by ATP and spontaneously also disappears in time in a physiological setting of incubation. ATP does not affect at all the binding capacity of non-glycosylated Grp94. However, complexes that native, partially glycosylated Grp94 forms with IgG in the presence of ATP show strikingly different characteristics with respect to those formed in absence of ATP. Results have relevance for the mechanism regulating the formation of stable Grp94-IgG complexes in vivo, in the pathological conditions associated with the extra-cellular location of Grp94.
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Jiang J, Xie D, Zhang W, Xiao G, Wen J. Fusion of Hsp70 to Mage-a1 enhances the potency of vaccine-specific immune responses. J Transl Med 2013; 11:300. [PMID: 24314011 PMCID: PMC4029478 DOI: 10.1186/1479-5876-11-300] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 11/27/2013] [Indexed: 11/17/2022] Open
Abstract
Background Heat shock proteins (HSPs) are capable of promoting antigen presentation of chaperoned peptides through interactions with receptors on antigen presenting cells. This property of HSPs suggests a potential function as an adjuvant-free carrier to stimulate immune responses against a covalently linked fusion partner. MAGE-A1 is a likely candidate for tumor immunotherapy due to its abundant immunogenic epitopes and strict tumor specificity. To analyze the influence of HSP70 conjugation to MAGE-A1, towards developing a novel effective vaccine against MAGE-expressing tumors, we cloned the murine counterpart of the human HSP70 and MAGE-A1 genes. Methods Recombinant proteins expressing Mage-a1 (aa 118–219), Hsp70, and Mage-a1-Hsp70 fusion were purified and used to immunize C57BL/6 mice. The humoral and cellular responses elicited against Mage-a1 were measured by ELISA, IFN-γ ELISPOT assay, and cytotoxicity assay. Results Immunization of mice with Mage-a1-Hsp70 fusion protein elicited significantly higher Mage-a1-specific antibody titers than immunization with either Mage-a1 alone or a combination of Mage-a1 + Hsp70. The frequency of IFN-γ-producing cells and the cytotoxic T lymphocyte (CTL) activity was also elevated. Consistent with the elevated immune response, immunization with fusion protein induced potent in vivo antitumor immunity against MAGE-a1-expressing tumors. Conclusions These results indicate that the fusion of Hsp70 to Mage-a1 can enhance immune responses and anti-tumor effects against Mage-a1-expressing tumors. Fusion of HSP70 to a tumor antigen may greatly enhance the potency of protein vaccines and can potentially be applied to other cancer systems with known tumor-specific antigens. These findings provide a scientific basis for the development of a novel HSP70 and MAGE fusion protein vaccine against MAGE-expressing tumors.
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Affiliation(s)
- Juhong Jiang
- Department of Pathology, The First Affiliated Hospital, Guangzhou Medical University, 151, Yanjiang Road, Guangzhou 510120, China.
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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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Je JH, Kim DY, Roh HJ, Pak C, Kim DH, Byamba D, Jee H, Kim TG, Park JM, Lee SK, Lee MG. The Antioxidative Effect of Heat-Shock Protein 70 in Dendritic Cells. Scand J Immunol 2013; 78:238-47. [DOI: 10.1111/sji.12078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 04/28/2013] [Indexed: 12/29/2022]
Affiliation(s)
- J. H. Je
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - D. Y. Kim
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - H. J. Roh
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - C. Pak
- Medical Mission Center; Yonsei University Health System; Seoul Korea
| | - D. H. Kim
- Department of Dermatology; CHA University College of Medicine; Seongnam Korea
| | - D. Byamba
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - H. Jee
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - T.-G. Kim
- Department of Environmental Medical Biology; Institute of Tropical Medicine; Yonsei University College of Medicine; Seoul Korea
| | - J. M. Park
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - S.-K. Lee
- Department of Biotechnology; College of Life Science and Biotechnology; National Creative Research Initiatives Center For Inflammatory Response Modulation; Yonsei University; Seoul Korea
| | - M.-G. Lee
- Department of Dermatology and Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
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Terracciano S, Chini MG, Piaz FD, Vassallo A, Riccio R, Bruno I, Bifulco G. Dimeric and trimeric triazole based molecules as a new class of Hsp90 molecular chaperone inhibitors. Eur J Med Chem 2013; 65:464-76. [DOI: 10.1016/j.ejmech.2013.05.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Revised: 05/14/2013] [Accepted: 05/15/2013] [Indexed: 01/05/2023]
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Mosca F, Romano N, Malatesta D, Ceccarelli G, Brunetti A, Bulfon C, Volpatti D, Abelli L, Galeotti M, Falconi A, Tiscar PG. Heat shock protein 70 kDa (HSP70) increase in sea bass (Dicentrarchus labrax, L 1758) thymus after vaccination against Listonella anguillarum. FISH PHYSIOLOGY AND BIOCHEMISTRY 2013; 39:615-626. [PMID: 23053607 DOI: 10.1007/s10695-012-9724-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Accepted: 09/24/2012] [Indexed: 06/01/2023]
Abstract
Heat shock proteins 70 kDa (HSP70) and apoptosis were investigated in thymus of sea bass juveniles (Dicentrarchus labrax) subsequently to a vaccination against Listonella (syn. Vibrio) anguillarum. HSP70 expression was measured by immunohistochemistry and immunoenzymatic methods, resulting in increase in HSP70 after bath immunization and persistent in fish exposed to an intraperitoneal (i.p.) booster. The HSP70 increase in thymus was suggested as induction in lymphocytic cells, to be related to immune system stimulation after vaccination. However, a thymic recruitment of lymphocyte subpopulations, characterized by higher expression of HSP70, was also hypothesized after vaccination. No apparent relationships were found between HSP70 and apoptosis. In fact, the vaccination did not modulate the apoptosis response, as measured by TUNEL assay and by immunohistochemistry for active caspase-3 expression. The lack of apoptosis effects could be ascribed to the use of inactivated bacteria that appeared not able to interfere with programmed cell death mechanisms. This manuscript aims to contribute to the knowledge of some biochemical features underlying the immunization, with a particular emphasis on the modulation of HSP70. However, further parameters involved in innate/adaptative immunity and apoptosis pathways have to be taken into account to well establish the functional role of HSP70 in fish vaccination.
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Affiliation(s)
- Francesco Mosca
- Dipartimento di Scienze Biomediche Comparate, P.zza A. Moro 45, 64100 Teramo, Italy
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Human hsp70 and HPV16 oE7 fusion protein vaccine induces an effective antitumor efficacy. Oncol Rep 2013; 30:407-12. [PMID: 23660931 DOI: 10.3892/or.2013.2445] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 04/04/2013] [Indexed: 11/05/2022] Open
Abstract
The persistent infection by human papilloma virus (HPV) is considered to be the major risk factor of cervical cancer, which is one of the most common cancers in women worldwide. Millions of women are currently infected with high-risk HPV. Thus, it is urgent to develop therapeutic vaccines to eliminate established infection or HPV-related diseases. In the present study, we constructed a very promising therapeutic HPV16 protein vaccine of optimized E7 (oE7)/huhsp70 using human hsp70 linked to HPV16 oE7. Our results demonstrated that vaccination with the oE7/huhsp70 protein vaccine induced a very strong E7-specific CD8(+) T cell immune response and resulted in a significant therapeutic effect against E7-expressing tumor cells. Our study verifies that huhsp70 is an effective immune adjuvant in the development of tumor therapeutic protein vaccines, and emphasizes that homologous huhsp70 is a promising tool in future human clinical applications.
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Li HZ, Li CW, Li CY, Zhang BF, Li LT, Li JM, Zheng JN, Chang JW. Isolation and identification of renal cell carcinoma-derived peptides associated with GP96. Technol Cancer Res Treat 2013; 12:285-93. [PMID: 23448575 DOI: 10.7785/tcrt.2012.500326] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We determined the possible associated determinants and analyzed whether gp96-_associated antigenic peptides can be found in renal cell carcinoma (RCC). The gp96-peptide complexes were chromatographically purified from resected tumor tissue of RCC patients. SDS-PAGE and Western blot analysis confirmed gp96 using the gp96 monoclonal antibody, and its concentration was measured using BCA. Approximately 20 to 50 μg gp96-peptide complexes was obtained from 1 g RCC tissue. The mass spectrometry (MS) analysis of the eluted peptides included the initial profiling using matrix-assisted laser desorption/ionization time-of-flight MS. Quadrupole time-of-flight MS combined with the Mascot search engine was used to identify the peptides and find proteins from primary sequence databases. MS analysis results demonstrated that the mass range of peptide associated with gp96 was from 1046.48 to 3501.56 Da. Further research confirmed the sequences of two gp96-associated peptides, namely, LVPLEGWGGNVM and PPVYYVPYVVL. However, the original protein of the two peptides could not be found. The results demonstrated that the gp96-associated peptides are small molecular peptides, and the two peptides are deduced to be RCC-associated peptides. The identified peptides were confirmed to be associated with gp96 using the protocols described above. However, the specificity and relevance of the association to the immunogenicity of gp96 remains to be examined. Further analysis must be accomplished before the findings can be applied in peptide vaccine.
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Affiliation(s)
- H-Z Li
- Jiangsu Key Laboratory of _Biological Cancer Therapy, Xuzhou Medical College, Huaihai Xi Road, Xuzhou, 221002, PR China.
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Panzarini E, Inguscio V, Dini L. Immunogenic cell death: can it be exploited in PhotoDynamic Therapy for cancer? BIOMED RESEARCH INTERNATIONAL 2012; 2013:482160. [PMID: 23509727 PMCID: PMC3591131 DOI: 10.1155/2013/482160] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Revised: 09/18/2012] [Accepted: 10/01/2012] [Indexed: 12/22/2022]
Abstract
Immunogenic Cell Death (ICD) could represent the keystone in cancer management since tumor cell death induction is crucial as well as the control of cancer cells revival after neoplastic treatment. In this context, the immune system plays a fundamental role. The concept of Damage-Associated Molecular Patterns (DAMPs) has been proposed to explain the immunogenic potential of stressed or dying/dead cells. ICD relies on DAMPs released by or exposed on dying cells. Once released, DAMPs are sensed by immune cells, in particular Dendritic Cells (DCs), acting as activators of Antigen-Presenting Cells (APCs), that in turn stimulate both innate and adaptive immunity. On the other hand, by exposing DAMPs, dying cancer cells change their surface composition, recently indicated as vital for the stimulation of the host immune system and the control of residual ill cells. It is well established that PhotoDynamic Therapy (PDT) for cancer treatment ignites the immune system to elicit a specific antitumor immunity, probably linked to its ability in inducing exposure/release of certain DAMPs, as recently suggested. In the present paper, we discuss the DAMPs associated with PDT and their role in the crossroad between cancer cell death and immunogenicity in PDT.
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Affiliation(s)
| | | | - Luciana Dini
- Department of Biological and Environmental Science and Technology (Di.S.Te.B.A.), University of Salento, Via per Monteroni, 73100 Lecce, Italy
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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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HSP70 and HSP90 Differentially Regulate Translocation of Extracellular Antigen to the Cytosol for Cross-Presentation. Autoimmune Dis 2012; 2012:745962. [PMID: 23050124 PMCID: PMC3462380 DOI: 10.1155/2012/745962] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 08/17/2012] [Indexed: 11/18/2022] Open
Abstract
Antigens (Ag) from cancer or virus-infected cells must be internalized by dendritic cells (DCs) to be presented to CD8+ T cells, which eventually differentiate into Ag-specific cytotoxic T lymphocytes (CTLs) that destroy cancer cells and infected cells. This pathway is termed cross-presentation and is also implicated as an essential step in triggering autoimmune diseases such as Type I diabetes. Internalized Ag locates within endosomes, followed by translocation through a putative pore structure spanning endosomal membranes into the cytosol, where it is degraded by the proteasome to generate antigen peptides. During translocation, Ag is believed to be unfolded since the pore size is too narrow to accept native Ag structure. Here, we show that paraformaldehyde-fixed, structurally inflexible Ag is less efficient in cross-presentation because of diminished translocation into the cytosol, supporting the “unfolded Ag” theory. We also show that HSP70 inhibitors block both endogenous and cross-presentation. ImageStream analysis revealed that the inhibition in cross-presentation is not due to blocking of Ag translocation because a HSP70 inhibitor rather facilitates the translocation, which is in marked contrast to the effect of an HSP90 inhibitor that blocks Ag translocation. Our results indicate that Ag translocation to the cytosol in cross-presentation is differentially regulated by HSP70 and HSP90.
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Shipman M, Lubick K, Fouchard D, Guram R, Grieco P, Jutila M, Dratz EA. Proteomic and systems biology analysis of monocytes exposed to securinine, a GABA(A) receptor antagonist and immune adjuvant. PLoS One 2012; 7:e41278. [PMID: 23028424 PMCID: PMC3441550 DOI: 10.1371/journal.pone.0041278] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 06/19/2012] [Indexed: 11/18/2022] Open
Abstract
Securinine, a GABA(A) receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABA(A) receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5'-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca(2+) binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants.
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Affiliation(s)
- Matt Shipman
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, United States of America.
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Frey B, Stache C, Rubner Y, Werthmöller N, Schulz K, Sieber R, Semrau S, Rödel F, Fietkau R, Gaipl US. Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential. J Immunotoxicol 2012; 9:301-13. [PMID: 22800185 DOI: 10.3109/1547691x.2012.693547] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chemotherapeutic agents (CT) and ionizing radiation (X-ray) induce DNA damage and primarily aim to stop the proliferation of tumor cells. However, multimodal anti-cancer therapies should finally result in tumor cell death and, best, in the induction of systemic anti-tumor immunity. Since distinct therapy-induced tumor cell death forms may create an immune activating tumor microenvironment, this study examined whether sole treatment with CT that are used in the therapy for colorectal cancer or in combination with X-ray result in colorectal tumor cell death with immunogenic potential. 5-Fluorouracil (5-FU), Oxaliplatin (Oxp), or Irinotecan (Irino) in combination with X-ray were all potent inhibitors of colorectal tumor cell colony formation. This study then examined the forms of cell death with AnnexinA5-FITC/Propidium Iodide staining. Necrosis was the prominent form of cell death induced by CT and/or X-ray. While only a combination of Irino with X-ray leads to death induction already 1 day after treatment, also the combinations of Oxp or 5-FU with X-ray and X-ray alone resulted in high necrosis rates at later time points after treatment. Inhibition of apoptosis increased the amount of necrotic tumor cells, suggesting that a programmed form of necrosis can be induced by CT + X-ray. 5-FU and Oxp alone or in combination with X-ray and Irino plus X-ray were most effective in increasing the expression of RIP, IRF-5, and p53, proteins involved in necrotic and apoptotic cell death pathways. All treatments further resulted in the release of the immune activating danger signals high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). The supernatants of the treated tumor cells induced maturation of dendritic cells. It is, therefore, concluded that combination of CT with X-ray is capable of inducing in vitro cell death forms of colorectal tumors with immunogenic potential.
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Affiliation(s)
- Benjamin Frey
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Germany
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Frey B, Weiss EM, Rubner Y, Wunderlich R, Ott OJ, Sauer R, Fietkau R, Gaipl US. Old and new facts about hyperthermia-induced modulations of the immune system. Int J Hyperthermia 2012; 28:528-42. [PMID: 22690925 DOI: 10.3109/02656736.2012.677933] [Citation(s) in RCA: 178] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Hyperthermia (HT) is a potent sensitiser for radiotherapy (RT) and chemotherapy (CT) and has been proven to modulate directly or indirectly cells of the innate and adaptive immune system. We will focus in this article on how anti-tumour immunity can be induced by HT. In contrast to some in vitro assays, in vivo examinations showed that natural killer cells and phagocytes like granulocytes are directly activated against the tumour by HT. Since heat also activates dendritic cells (DCs), HT should be combined with further death stimuli (RT, CT or immune therapy) to allocate tumour antigen, derived from, for example, necrotic tumour cells, for uptake by DCs. We will outline that induction of immunogenic tumour cells and direct tumour cell killing by HT in combination with other therapies contributes to immune activation against the tumour. Studies will be presented showing that non-beneficial effects of HT on immune cells are mostly timely restricted. A special focus is set on immune activation mediated by extracellular present heat shock proteins (HSPs) carrying tumour antigens and further danger signals released by dying tumour cells. Local HT treatment in addition to further stress stimuli exerts abscopal effects and might be considered as in situ tumour vaccination. An increased natural killer (NK) cell activity, lymphocyte infiltration and HSP-mediated induction of immunogenic tumour cells have been observed in patients. Treatments with the addition of HT therefore can be considered as a personalised cancer treatment approach by specifically activating the immune system against the individual unique tumour.
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Affiliation(s)
- Benjamin Frey
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Germany
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Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 2012; 39:323-39. [PMID: 22595055 PMCID: PMC3356994 DOI: 10.1053/j.seminoncol.2012.02.006] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Therapeutic cancer vaccines are a unique treatment modality in that they initiate a dynamic process of activating the host immune system, which can then be exploited by concurrent or subsequent therapies. The addition of immunotherapy to standard-of-care cancer therapies has shown evidence of efficacy in preclinical models and in the clinical setting. This review examines the preclinical and clinical interactions between vaccine-mediated tumor-specific immune responses and local radiation, systemic chemotherapy, or select small molecule inhibitors, as well as the potential synergy between these modalities.
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Affiliation(s)
- James W Hodge
- Recombinant Vaccine Group, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Randazzo M, Terness P, Opelz G, Kleist C. Active-specific immunotherapy of human cancers with the heat shock protein Gp96-revisited. Int J Cancer 2012; 130:2219-31. [PMID: 22052568 DOI: 10.1002/ijc.27332] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 10/05/2011] [Indexed: 12/20/2022]
Abstract
The passive administration of specific antibodies that selectively target tumors is a well-known strategy in cancer treatment. Active immunotherapy using peptide vaccines, in contrast, is expected to induce specific, cytolytic T cells in the patient, which react against tumor antigens and destroy malignant cells. Although several concepts exist, the identification and low immunogenicity of tumor-specific peptides remain a serious problem. Heat shock proteins (HSPs), notably glycoprotein (Gp) 96, are of special interest, because they are able to take molecular peptide-fingerprints of the protein array characteristic for a particular cell. Association of Gp96 with peptides has been shown to be essential for crosspresentation and activation of T cells. Consequently, Gp96-peptide complexes extracted from cancer cells harbor the tumor-specific peptides and are immunogenic, thus offering a tool for active immunization against the tumor. Already, several immunotherapy studies of human cancers have been carried out, showing no severe adverse effects but unfortunately only limited improvement in the clinical outcome. Vitespen, a commercial HSP-peptide complex vaccine based on tumor-derived Gp96, seems to induce an improved overall survival for subsets of early stage melanoma and kidney cancer patients. The limited access to vaccine material derived from the autologous tumor requires the development of alternative protocols. Moreover, counteracting immunosuppressive mechanisms induced by the malignancy might further improve the efficacy of vaccinations. This review critically analyzes the current state of clinical immunotherapy with Gp96, with special attention to Vitespen.
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Affiliation(s)
- Marco Randazzo
- Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany
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Abstract
The ubiquitin-proteasomal system is an essential element of the protein quality control machinery in cells. The central part of this system is the 20S proteasome. The proteasome is a barrel-shaped multienzyme complex, containing several active centers hidden at the inner surface of the hollow cylinder. So, the regulation of the substrate entry toward the inner proteasomal surface is a key control mechanism of the activity of this protease. This chapter outlines the knowledge on the structure of the subunits of the 20S proteasome, the binding and structure of some proteasomal regulators and inducible proteasomal subunits. Therefore, this chapter imparts the knowledge on proteasomal structure which is required for the understanding of the following chapters.
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Jolesch A, Elmer K, Bendz H, Issels RD, Noessner E. Hsp70, a messenger from hyperthermia for the immune system. Eur J Cell Biol 2012; 91:48-52. [DOI: 10.1016/j.ejcb.2011.02.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 02/01/2011] [Accepted: 02/01/2011] [Indexed: 12/29/2022] Open
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Immunotherapy of brain cancers: the past, the present, and future directions. Clin Dev Immunol 2011; 2010:296453. [PMID: 21437175 PMCID: PMC3061456 DOI: 10.1155/2010/296453] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Accepted: 12/30/2010] [Indexed: 11/17/2022]
Abstract
Treatment of brain cancers, especially high grade gliomas (WHO stage III and IV) is slowly making progress, but not as fast as medical researchers and the patients would like. Immunotherapy offers the opportunity to allow the patient's own immune system a chance to help eliminate the cancer. Immunotherapy's strength is that it efficiently treats relatively small tumors in experimental animal models. For some patients, immunotherapy has worked for them while not showing long-term toxicity. In this paper, we will trace the history of immunotherapy for brain cancers. We will also highlight some of the possible directions that this field may be taking in the immediate future for improving this therapeutic option.
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