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Chen J, Wang S, Ding Y, Xu D, Zheng S. Radiotherapy-induced alterations in tumor microenvironment: metabolism and immunity. Front Cell Dev Biol 2025; 13:1568634. [PMID: 40356601 PMCID: PMC12066526 DOI: 10.3389/fcell.2025.1568634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.
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Affiliation(s)
- Jinpeng Chen
- Department of General Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
- Southeast University Medical School, Nanjing, Jiangsu, China
| | - Sheng Wang
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu, China
| | - Yue Ding
- Department of General Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
- Southeast University Medical School, Nanjing, Jiangsu, China
| | - Duo Xu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shiya Zheng
- Southeast University Medical School, Nanjing, Jiangsu, China
- Department of Oncology, Southeast University, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
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2
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Lu S, Yang Y, Song Z, Cao J, Han Z, Chen L, He Y, Wang J, Teng Y, Zhang Z, Zou J, Ge J, Yang H, Cheng L. Dual functional nanoplatforms potentiate osteosarcoma immunotherapy via microenvironment modulation. Natl Sci Rev 2025; 12:nwaf002. [PMID: 39936146 PMCID: PMC11812574 DOI: 10.1093/nsr/nwaf002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/13/2024] [Accepted: 01/06/2025] [Indexed: 02/13/2025] Open
Abstract
Osteosarcoma (OS), a highly aggressive bone tumor, presents significant challenges in terms of effective treatment. We identified that cellular autophagy was impaired within OS by comparing clinical OS samples through bioinformatic analyses and further validated the inhibition of mitochondrial autophagy in OS at the transcriptomic level. Based on this finding, we investigated the therapeutic potential of a dual functional metal nanoplatform (MnSx) to facilitate a transition from the protective effect of low-level autophagy in OS to the killing effect of high-level autophagy in OS. MnSx facilitated intracellular H2S generation via endocytosis, leading to the S-sulfhydration of ubiquitin-specific peptidase 8 (USP8) and subsequent promotion of mitochondrial autophagy in vitro. Additionally, MnSx activated the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway, further enhancing the cellular autophagic response and accelerating tumor cell death. Moreover, it was demonstrated in vivo that MnSx, on the one hand, mediated the activation of tumor autophagy by USP8 via intracellular H2S, while Mn2+ promoted the maturation of dendritic cells, activated cytotoxic T lymphocytes and contributed to tumor eradication. Such tumor killing could be suppressed by the autophagy inhibitor chloroquine. Importantly, synergistic combination therapy with immune checkpoint inhibitors showed promise for achieving complete remission of OS. This study highlights the potential of MnSx as a dual-functional therapeutic platform for OS treatment and offers novel directions for future research in this field.
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Affiliation(s)
- Shunyi Lu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yuqi Yang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Zhuorun Song
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Jie Cao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Zhihui Han
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Linfu Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Yunfei He
- Soochow University Institues for Translational Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
| | - Jiayi Wang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yun Teng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
| | - Zengli Zhang
- Department of Environmental Health School of Public Health, Soochow University, Suzhou 215123, China
| | - Jun Zou
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
| | - Jun Ge
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215123, China
| | - Liang Cheng
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
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3
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Li Z, Yang Y, Zong J, Zhang B, Li X, Qi H, Yu T, Li Y. Dendritic cells immunotargeted therapy for atherosclerosis. Acta Pharm Sin B 2025; 15:792-808. [PMID: 40177571 PMCID: PMC11959979 DOI: 10.1016/j.apsb.2024.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/15/2024] [Accepted: 11/20/2024] [Indexed: 04/05/2025] Open
Abstract
Atherosclerosis, a chronic inflammatory disease, is markedly influenced by both immune and inflammatory reactions throughout its progression. Dendritic cells, as pivotal antigen-presenting entities, play a crucial role in the initiation of immune responses and the preservation of immunological homeostasis. Accumulating data indicates that dendritic cells are present in healthy arteries and accumulate significantly in atherosclerotic plaques. Novel immunotherapeutic approaches and vaccination protocols have yielded substantial clinical advancements in managing chronic inflammatory diseases, with dendritic cell-centric modalities emerging for atherosclerotic management. In this review, we delineate the essential functions and underlying mechanisms of dendritic cells and their subsets in the modulation of atherosclerotic inflammation and immune responses. We underscore the immense promise of dendritic cell-based immunotherapeutic strategies, including vaccines and innovative combinations with nanotechnological drug delivery platforms for atherosclerosis treatment. We also discuss the challenges associated with dendritic cell immunotherapy and provide perspectives on the future direction of this field.
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Affiliation(s)
- Zhaohui Li
- Department of Vascular Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266400, China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jinbao Zong
- Clinical Laboratory, Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, 266000, China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiaolu Li
- Department of Cardiac Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hongzhao Qi
- Institute for Translational Medicine, the Affiliated Hospital of Qingdao University, Qingdao, 266021, China
| | - Tao Yu
- Department of Cardiac Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
- Institute for Translational Medicine, the Affiliated Hospital of Qingdao University, Qingdao, 266021, China
| | - Yongxin Li
- Department of Vascular Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266400, China
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4
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Liao KL, Wieler AJ, Gascon PML. Mathematical modeling and analysis of cancer treatment with radiation and anti-PD-L1. Math Biosci 2024; 374:109218. [PMID: 38797473 DOI: 10.1016/j.mbs.2024.109218] [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: 02/10/2024] [Revised: 05/12/2024] [Accepted: 05/16/2024] [Indexed: 05/29/2024]
Abstract
In cancer treatment, radiation therapy (RT) induces direct tumor cell death due to DNA damage, but it also enhances the deaths of radiosensitive immune cells and is followed by local relapse and up-regulation of immune checkpoint ligand PD-L1. Since the binding between PD-1 and PD-L1 curtails anti-tumor immunities, combining RT and PD-L1 inhibitor, anti-PD-L1, is a potential method to improve the treatment efficacy by RT. Some experiments support this hypothesis by showing that the combination of ionizing irradiation (IR) and anti-PD-L1 improves tumor reduction comparing to the monotherapy of IR or anti-PD-L1. In this work, we create a simplified ODE model to study the order of tumor growths under treatments of IR and anti-PD-L1. Our synergy analysis indicates that both IR and anti-PD-L1 improve the tumor reduction of each other, when IR and anti-PD-L1 are given simultaneously. When giving IR and anti-PD-L1 separately, a high dosage of IR should be given first to efficiently reduce tumor load and then followed by anti-PD-L1 with strong efficacy to maintain the tumor reduction and slow down the relapse. Increasing the duration of anti-PD-L1 improves the tumor reduction, but it cannot prolong the duration that tumor relapses to the level of the control case. Under some simplification, we also prove that the model has an unstable tumor free equilibrium and a locally asymptotically stable tumor persistent equilibrium. Our bifurcation diagram reveals a transition from tumor elimination to tumor persistence, as the tumor growth rate increases. In the tumor persistent case, both anti-PD-L1 and IR can reduce tumor amount in the long term.
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Affiliation(s)
- Kang-Ling Liao
- Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada.
| | - Adam J Wieler
- Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada
| | - Pedro M Lopez Gascon
- Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada
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5
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Bai L, Yang J, Yu S, Xiang Z, Zeng Y, Shen M, Kou X, Wu Q, Gong C. Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses. Acta Pharm Sin B 2024; 14:821-835. [PMID: 38322329 PMCID: PMC10840429 DOI: 10.1016/j.apsb.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/21/2023] [Accepted: 08/08/2023] [Indexed: 02/08/2024] Open
Abstract
Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H2O2), which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.
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Affiliation(s)
| | | | - Siting Yu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhongzheng Xiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuanyuan Zeng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Meiling Shen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaorong Kou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qinjie Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Changyang Gong
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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Luo H, Sun Y, Wang L, Liu H, Zhao R, Song M, Ge H. Targeting endoplasmic reticulum associated degradation pathway combined with radiotherapy enhances the immunogenicity of esophageal cancer cells. Cancer Biol Ther 2023; 24:2166763. [PMID: 36907982 PMCID: PMC10026871 DOI: 10.1080/15384047.2023.2166763] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 12/15/2022] [Accepted: 01/03/2023] [Indexed: 03/14/2023] Open
Abstract
Immunogenic cell death (ICD) is essential for the activation of immune system against cancer. We aimed to investigate the efficacy of endoplasmic reticulum (ER)-associated protein degradation (ERAD) inhibitors (EerI and NMS-873) in enhancing radiation-induced ICD in esophageal cancer (EC). EC cells were administered with ERAD inhibitors, radiation therapy (RT), and the combination treatment. ICD hallmarks including calreticulin (CALR), adenosine triphosphate (ATP), and high mobility group protein B1 (HMGB1) were detected. The efficacy of ERAD inhibitors combined with RT in stimulating ICD was analyzed. Additionally, the role of ICD hallmarks in immune cell infiltration and patient survival was investigated. Inhibiting ERAD pathways was able to stimulate ICD component emission from dying EC cells in a dose-dependent pattern. Radiation-induced ICD was significantly increased after high doses RT (≥10 Gy). ERAD inhibitor combined with moderate dose RT (≥6 Gy) was capable of stimulating increased ICD in EC cells. Dual therapy could elicit the antitumor immune response by enhancing dendritic cells maturation and phagocytosis. Further investigation revealed a significant correlation between CALR and tumor-infiltrating immune cells. Low expression of ATP and HMGB1 and high expression of CALR were associated with favorable survival in patients with EC. The immunogenicityof EC can be enhanced by ERAD inhibitors combined with moderate doses of RT. ICD hallmark genes, especially CALR, are correlated to immune cell infiltration and clinical outcomes in EC. The present results demonstrated an important method to improve the immunogenicity of EC cells for enhanced antitumor immune response.
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Affiliation(s)
- Hui Luo
- Laboratory of Radiation Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Sun
- Laboratory of Radiation Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Liuxiang Wang
- Academic of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Hui Liu
- Department of Basic Medicine, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Ran Zhao
- Department of Basic Medicine, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Mengqiu Song
- Department of Basic Medicine, China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Hong Ge
- Laboratory of Radiation Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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7
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Liao KL, Watt KD, Protin T. Different mechanisms of CD200-CD200R induce diverse outcomes in cancer treatment. Math Biosci 2023; 365:109072. [PMID: 37734537 DOI: 10.1016/j.mbs.2023.109072] [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: 06/20/2023] [Revised: 08/09/2023] [Accepted: 08/26/2023] [Indexed: 09/23/2023]
Abstract
The CD200 is a cell membrane protein expressed by tumor cells, and its receptor CD200 receptor (CD200R) is expressed by immune cells including macrophages and dendritic cells. The formation of CD200-CD200R inhibits the cellular functions of the targeted immune cells, so CD200 is one type of the immune checkpoint and blockade CD200-CD200R formation is a potential cancer treatment. However, the CD200 blockade has opposite treatment outcomes in different types of cancers. For instance, the CD200R deficient mice have a higher tumor load than the wild type (WT) mice in melanoma suggesting that CD200-CD200R inhibits melanoma. On the other hand, the antibody anti-CD200 treatment in pancreatic ductal adenocarcinoma (PDAC) and head and neck squamous cell carcinoma (HNSCC) significantly reduces the tumor load indicating that CD200-CD200R promotes PDAC and HNSCC. In this work, we hypothesize that different mechanisms of CD200-CD200R in tumor microenvironment could be one of the reasons for the diverse treatment outcomes of CD200 blockade in different types of cancers. We create one Ordinary Differential Equations (ODEs) model for melanoma including the inhibition of CCL8 and regulatory T cells and the switching from M2 to M1 macrophages by CD200-CD200R to capture the tumor inhibition by CD200-CD200R. We also create another ODEs model for PDAC and HNSCC including the promotion of the polarization and suppressive activities of M2 macrophages by CD200-CD200R to generate the tumor promotion by CD200-CD200R. Furthermore, we use these two models to investigate the treatment efficacy of the combination treatment between the CD200-CD200R blockade and the other immune checkpoint inhibitor, anti-PD-1. Our result shows that different mechanisms of CD200-CD200R can induce different treatment outcomes in combination treatments, namely, only the CD200-CD200R blockade reduces tumor load in melanoma and only the anti-PD-1 and CD200 knockout decrease tumor load in PDAC and HNSCC. Moreover, in melanoma, the CD200-CD200R mainly utilizes the inhibitions on M1 macrophages and dendritic cells to inhibit tumor growth, instead of M2 macrophages.
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Affiliation(s)
- Kang-Ling Liao
- Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada.
| | - Kenton D Watt
- Department of Mathematics, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada
| | - Tom Protin
- Department of Applied Mathematics, INSA Rennes, France
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Chen X, Liu Q, Wu E, Ma Z, Tuo B, Terai S, Li T, Liu X. The role of HMGB1 in digestive cancer. Biomed Pharmacother 2023; 167:115575. [PMID: 37757495 DOI: 10.1016/j.biopha.2023.115575] [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: 08/08/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 09/29/2023] Open
Abstract
High mobility group box protein B1 (HMGB1) belongs to the HMG family, is widely expressed in the nucleus of digestive mucosal epithelial cells, mesenchymal cells and immune cells, and binds to DNA to participate in genomic structural stability, mismatch repair and transcriptional regulation to maintain normal cellular activities. In the context of digestive inflammation and tumors, HMGB1 readily migrates into the extracellular matrix and binds to immune cell receptors to affect their function and differentiation, further promoting digestive tract tissue injury and tumor development. Notably, HMGB1 can also promote the antitumor immune response. Therefore, these seemingly opposing effects in tumors make targeted HMGB1 therapies important in digestive cancer. This review focuses on the role of HMGB1 in tumors and its effects on key pathways of digestive cancer and aims to provide new possibilities for targeted tumor therapy.
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Affiliation(s)
- Xiangqi Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Qian Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Enqing Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Shuji Terai
- Division of Gastroenterology & Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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Yao S, Han Y, Yang M, Jin K, Lan H. It's high-time to re-evaluate the value of induced-chemotherapy for reinforcing immunotherapy in colorectal cancer. Front Immunol 2023; 14:1241208. [PMID: 37920463 PMCID: PMC10619163 DOI: 10.3389/fimmu.2023.1241208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 10/09/2023] [Indexed: 11/04/2023] Open
Abstract
Immunotherapy has made significant advances in the treatment of colorectal cancer (CRC), revolutionizing the therapeutic landscape and highlighting the indispensable role of the tumor immune microenvironment. However, some CRCs have shown poor response to immunotherapy, prompting investigation into the underlying reasons. It has been discovered that certain chemotherapeutic agents possess immune-stimulatory properties, including the induction of immunogenic cell death (ICD), the generation and processing of non-mutated neoantigens (NM-neoAgs), and the B cell follicle-driven T cell response. Based on these findings, the concept of inducing chemotherapy has been introduced, and the combination of inducing chemotherapy and immunotherapy has become a standard treatment option for certain cancers. Clinical trials have confirmed the feasibility and safety of this approach in CRC, offering a promising method for improving the efficacy of immunotherapy. Nevertheless, there are still many challenges and difficulties ahead, and further research is required to optimize its use.
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Affiliation(s)
- Shiya Yao
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yuejun Han
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Mengxiang Yang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
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Huang J, Sun X, Wang Y, Su J, Li G, Wang X, Yang Y, Zhang Y, Li B, Zhang G, Li J, Du J, Nanjundappa RH, Umeshappa CS, Shao K. Biological interactions of polystyrene nanoplastics: Their cytotoxic and immunotoxic effects on the hepatic and enteric systems. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 264:115447. [PMID: 37690176 DOI: 10.1016/j.ecoenv.2023.115447] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/12/2023]
Abstract
As emerging pollutants in the environment, nanoplastics (NPs) can cross biological barriers and be enriched in organisms, posing a greatest threat to the health of livestock and humans. However, the size-dependent toxic effects of NPs in higher mammals remain largely unknown. To determine the size-dependent potential toxicities of NPs, we exposed mouse (AML-12) and human (L02) liver cell lines in vitro, and 6-week-old C57BL/6 mice (well-known preclinical model) in vivo to five different sizes of polystyrene NPs (PS-NPs) (20, 50, 100, 200 and 500 nm). We found that ultra-small NPs (20 nm) induced the highest cytotoxicity in mouse and human liver cell lines, causing oxidative stress and mitochondrial membrane potential loss on AML-12 cells. Unexpectedly in vivo, after long-term oral exposure to PS-NPs (75 mg/kg), medium NPs (200 nm) and large NPs (500 nm) induced significant hepatotoxicity, evidenced by increased oxidative stress, liver dysfunction, and lipid metabolism disorders. Most importantly, medium or large NPs generated local immunotoxic effects via recruiting and activating more numbers of neutrophils and monocytes in the liver or intestine, which potentially resulted in increased proinflammatory cytokine secretion and the tissue damage. The discrepancy in in vitro-in vivo toxic results might be attributed to the different properties of biodistribution and tissue accumulation of different sized NPs in vivo. Our study provides new insights regarding the hepatotoxicity and immunotoxicity of NPs on human and livestock health, warranting us to take immense measures to prevent these NPs-associated health damage.
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Affiliation(s)
- Jiahao Huang
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Xinbo Sun
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Yang Wang
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Jianlong Su
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Guangzhe Li
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Xu Wang
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Yuning Yang
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Yuxuan Zhang
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Bangjian Li
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Guanyi Zhang
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Jinrong Li
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
| | - Jing Du
- Liaoning Ocean and Fisheries Science Research Institute, 50# Heishijiao Road, Shahekou District, Dalian 116023, China
| | | | - Channakeshava Sokke Umeshappa
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pediatrics, IWK Research Center, Halifax, NS, Canada.
| | - Kun Shao
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.
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Lee KW, Yam JWP, Mao X. Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations. Cells 2023; 12:2147. [PMID: 37681880 PMCID: PMC10486560 DOI: 10.3390/cells12172147] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.
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Affiliation(s)
- Kyu-Won Lee
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
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12
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Liu Z, Xu X, Liu K, Zhang J, Ding D, Fu R. Immunogenic Cell Death in Hematological Malignancy Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207475. [PMID: 36815385 PMCID: PMC10161053 DOI: 10.1002/advs.202207475] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/09/2023] [Indexed: 05/06/2023]
Abstract
Although the curative effect of hematological malignancies has been improved in recent years, relapse or drug resistance of hematological malignancies will eventually recur. Furthermore, the microenvironment disorder is an important mechanism in the pathogenesis of hematological malignancies. Immunogenic cell death (ICD) is a unique mechanism of regulated cell death (RCD) that triggers an intact antigen-specific adaptive immune response by firing a set of danger signals or damage-associated molecular patterns (DAMPs), which is an immunotherapeutic modality with the potential for the treatment of hematological malignancies. This review summarizes the existing knowledge about the induction of ICD in hematological malignancies and the current research on combining ICD inducers with other treatment strategies for hematological malignancies.
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Affiliation(s)
- Zhaoyun Liu
- Department of HematologyTianjin Medical University General HospitalTianjin300052P. R. China
| | - Xintong Xu
- Department of HematologyTianjin Medical University General HospitalTianjin300052P. R. China
| | - Kaining Liu
- State Key Laboratory of Medicinal Chemical BiologyKey Laboratory of Bioactive, Materials, Ministry of Education and College of Life SciencesNankai UniversityTianjin300071P. R. China
| | - Jingtian Zhang
- State Key Laboratory of Medicinal Chemical BiologyKey Laboratory of Bioactive, Materials, Ministry of Education and College of Life SciencesNankai UniversityTianjin300071P. R. China
| | - Dan Ding
- State Key Laboratory of Medicinal Chemical BiologyKey Laboratory of Bioactive, Materials, Ministry of Education and College of Life SciencesNankai UniversityTianjin300071P. R. China
| | - Rong Fu
- Department of HematologyTianjin Medical University General HospitalTianjin300052P. R. China
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13
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Zhao Y, Li R. HMGB1 is a promising therapeutic target for asthma. Cytokine 2023; 165:156171. [PMID: 36924610 DOI: 10.1016/j.cyto.2023.156171] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/16/2023]
Abstract
High-mobility group box protein 1 (HMGB1) is a non-histone deoxyribonucleic acid-binding nuclear protein. In physiological state it is involved in gene transctioripn regulation and cell replication, differentiation and maturation. HMGB1 is actively secreted into the extracellular space in the form of intracellular vesicles, upon stimulation of inflammation and infection, by monocytes, macrophages, dendritic cells (DCs), and other immune cells, and can also be passively released by necrotic or injured cells. After binding with the corresponding receptors, HMGB1 can activate the downstream substrate and trigger a series of biological effects. HMGB1 was mainly dependent on toll-like re ceptors (TLR) 2 and 4, and receptors for advanced glycation end products (RAGE) to trigger intracellular signal transduction, and mediate innate and adoptive immune responses. Besides these, studies have reported the participation of TLR3, TLR9, T-cell immunoglobulin mucin (TIM) 3, CD24, anti-N-methyl-D-aspartate receptor (NMDAR) in Th2 inflammatory response, eosinophilic airway inflammation, and airway hyperresponsiveness, mediated by HMGB1 in asthma. Both clinical and experimental studies suggested that HMGB1 was involved in the pathogenesis of asthma probably by regulating the downstream signaling pathways via corresponding receptors. This article reviews the role of HMGB1 in pathogenesis of asthma, and provides a new theoretical basis for the diagnosis and treatment of asthma.
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Affiliation(s)
- Yue Zhao
- Department of Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology; Hubei Clinical Research Center for Infectious Diseases; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, PR China; The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, PR China
| | - Ruiting Li
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, PR China.
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14
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Ge J, Yang N, Yang Y, Yu H, Yang X, Wang Y, Wang T, Cheng S, Wang Y, Han Z, Teng Y, Zou J, Yang H, Cheng L. The combination of eddy thermal effect of biodegradable magnesium with immune checkpoint blockade shows enhanced efficacy against osteosarcoma. Bioact Mater 2023; 25:73-85. [PMID: 36733928 PMCID: PMC9883145 DOI: 10.1016/j.bioactmat.2023.01.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/02/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023] Open
Abstract
Osteosarcoma (OS) patients have a poor prognosis due to its high degree of heterogeneity and high rate of metastasis. Magnetic hyperthermia therapy (MHT) combined with immunotherapy is an effective strategy to treat solid and metastatic tumors. Here, we combined biodegradable magnesium (Mg) macroscale rods, which acted as an eddy thermo-magnetic agent under a low external alternating magnetic field, and immunotherapy to achieve a radical cure for OS. The eddy thermal effect (ETE) of the Mg rods (MgR) showed outstanding cytotoxic effects and enhanced the maturation of dendritic cells (DCs), and the mild MHT induced the immunogenic cell death (ICD) in the OS cells. Combined with immune checkpoint blockade (ICB) therapy, we obtained an excellent curative effect against OS, and a further evaluation demonstrated that the local MHT induced by the MgR increased T cells infiltration and the polarization of M1 macrophages. Interestingly, the biodegradable MgR also promoted bone osteogenesis. Our work highlighted the uneven ETE mediated by the biodegradable MgR induced a comprehensive immunologic activation in the OS tumor microenvironment (TME), which would inspire the application of MHT for the effective treatment of OS.
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Affiliation(s)
- Jun Ge
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China,Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Nailin Yang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Yuqi Yang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Hao Yu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaoyuan Yang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Yingjie Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tianyi Wang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shuning Cheng
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Yuanjie Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Zhihui Han
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China
| | - Yun Teng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jun Zou
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China,Corresponding author.
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China,Corresponding author.
| | - Liang Cheng
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, China,Corresponding author.
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15
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Li Z, Lai X, Fu S, Ren L, Cai H, Zhang H, Gu Z, Ma X, Luo K. Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201734. [PMID: 35652198 PMCID: PMC9353475 DOI: 10.1002/advs.202201734] [Citation(s) in RCA: 259] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/21/2022] [Indexed: 02/05/2023]
Abstract
Tumor immunotherapy is only effective in a fraction of patients due to a low response rate and severe side effects, and these challenges of immunotherapy in clinics can be addressed through induction of immunogenic cell death (ICD). ICD is elicited from many antitumor therapies to release danger associated molecular patterns (DAMPs) and tumor-associated antigens to facilitate maturation of dendritic cells (DCs) and infiltration of cytotoxic T lymphocytes (CTLs). The process can reverse the tumor immunosuppressive microenvironment to improve the sensitivity of immunotherapy. Nanostructure-based drug delivery systems (NDDSs) are explored to induce ICD by incorporating therapeutic molecules for chemotherapy, photosensitizers (PSs) for photodynamic therapy (PDT), photothermal conversion agents for photothermal therapy (PTT), and radiosensitizers for radiotherapy (RT). These NDDSs can release loaded agents at a right dose in the right place at the right time, resulting in greater effectiveness and lower toxicity. Immunotherapeutic agents can also be combined with these NDDSs to achieve the synergic antitumor effect in a multi-modality therapeutic approach. In this review, NDDSs are harnessed to load multiple agents to induce ICD by chemotherapy, PDT, PTT, and RT in combination of immunotherapy to promote the therapeutic effect and reduce side effects associated with cancer treatment.
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Affiliation(s)
- Zhilin Li
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Xiaoqin Lai
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Shiqin Fu
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Long Ren
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Hao Cai
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Hu Zhang
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
- Amgen Bioprocessing CentreKeck Graduate InstituteClaremontCA91711USA
| | - Zhongwei Gu
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Xuelei Ma
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - Kui Luo
- Department of BiotherapyHuaxi MR Research Center (HMRRC)Day Surgery CenterDepartment of RadiologyCancer CenterResearch Core Facilities of West China HospitalNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease‐Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
- Functional and Molecular Imaging Key Laboratory of Sichuan Provinceand Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China
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16
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Liao KL, Watt KD. Mathematical Modeling and Analysis of CD200-CD200R in Cancer Treatment. Bull Math Biol 2022; 84:82. [PMID: 35792958 DOI: 10.1007/s11538-022-01039-x] [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: 10/08/2021] [Accepted: 06/01/2022] [Indexed: 11/26/2022]
Abstract
CD200 is a cell membrane protein that binds to its receptor, CD200 receptor (CD200R). The CD200 positive tumor cells inhibit the cellular functions of M1 and M2 macrophages and dendritic cells (DCs) through the CD200-CD200R complex, resulting in downregulation of Interleukin-10 and Interleukin-12 productions and affecting the activation of cytotoxic T lymphocytes. In this work, we provide two ordinary differential equation models, one complete model and one simplified model, to investigate how the binding affinities of CD200R and the populations of M1 and M2 macrophages affect the functions of the CD200-CD200R complex in tumor growth. Our simulations demonstrate that (i) the impact of the CD200-CD200R complex on tumor promotion or inhibition highly depends on the binding affinity of the CD200R on M2 macrophages and DCs to the CD200 on tumor cells, and (ii) a stronger binding affinity of the CD200R on M1 macrophages or DCs to the CD200 on tumor cells induces a higher tumor cell density in the CD200 positive tumor. Thus, the CD200 blockade would be an efficient treatment method in this case. Moreover, the simplified model shows that the binding affinity of CD200R on macrophages is the major factor to determine the treatment efficacy of CD200 blockade when the binding affinities of CD200R on M1 and M2 macrophages are significantly different to each other. On the other hand, both the binding affinity of CD200R and the population of macrophages are the major factors to determine the treatment efficacy of CD200 blockade when the binding affinities of CD200R on M1 and M2 macrophages are close to each other. We also analyze the simplified model to investigate the dynamics of the positive and trivial equilibria of the CD200 positive tumor case and the CD200 deficient tumor case. The bifurcation diagrams show that when M1 macrophages dominate the population, the tumor cell density of the CD200 positive tumor is higher than the one of CD200 deficient tumor. Moreover, the dynamics of tumor cell density change from tumor elimination to tumor persistence to oscillation, as the maximal proliferation rate of tumor cells increases.
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Affiliation(s)
- Kang-Ling Liao
- Department of Mathematics, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
| | - Kenton D Watt
- Department of Mathematics, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada
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17
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Jankauskaite L, Malinauskas M, Mickeviciute GC. HMGB1: A Potential Target of Nervus Vagus Stimulation in Pediatric SARS-CoV-2-Induced ALI/ARDS. Front Pediatr 2022; 10:884539. [PMID: 35633962 PMCID: PMC9132499 DOI: 10.3389/fped.2022.884539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/11/2022] [Indexed: 12/19/2022] Open
Abstract
From the start of pandemics, children were described as the ones who were less affected by SARS-Cov-2 or COVID-19, which was mild in most of the cases. However, with the growing vaccination rate of the adult population, children became more exposed to the virus and more cases of severe SARS-CoV-2-induced ARDS are being diagnosed with the disabling consequences or lethal outcomes associated with the cytokine storm. Thus, we do hypothesize that some of the children could benefit from nervus vagus stimulation during COVID-19 ARDS through the inhibition of HMGB1 release and interaction with the receptor, resulting in decreased neutrophil accumulation, oxidative stress, and coagulopathy as well as lung vascular permeability. Moreover, stimulation through alpha-7 nicotinic acetylcholine receptors could boost macrophage phagocytosis and increase the clearance of DAMPs and PAMPs. Further rise of FGF10 could contribute to lung stem cell proliferation and potential regeneration of the injured lung. However, this stimulation should be very specific, timely, and of proper duration, as it could lead to such adverse effects as increased viral spread and systemic infection, especially in small children or infants due to specific pediatric immunity state and anatomical features of the respiratory system.
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Affiliation(s)
- Lina Jankauskaite
- Lithuanian University of Health Sciences, Medical Academy, Pediatric Department, Kaunas, Lithuania
- Lithuanian University of Health Sciences, Medical Academy, Institute of Physiology and Pharmacology, Kaunas, Lithuania
| | - Mantas Malinauskas
- Lithuanian University of Health Sciences, Medical Academy, Institute of Physiology and Pharmacology, Kaunas, Lithuania
| | - Goda-Camille Mickeviciute
- Lithuanian University of Health Sciences, Medical Academy, Pediatric Department, Kaunas, Lithuania
- Lithuanian University of Health Sciences, Medical Academy, Institute of Physiology and Pharmacology, Kaunas, Lithuania
- Rehabilitation Center “Palangos Linas”, Palanga, Lithuania
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18
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A Monoclonal Anti-HMGB1 Antibody Attenuates Neurodegeneration in an Experimental Animal Model of Glaucoma. Int J Mol Sci 2022; 23:ijms23084107. [PMID: 35456925 PMCID: PMC9028318 DOI: 10.3390/ijms23084107] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 02/06/2023] Open
Abstract
Neuroinflammation is a crucial process for the loss of retinal ganglion cells (RGC), a major characteristic of glaucoma. High expression of high-mobility group box protein 1 (HMGB1) plays a detrimental role in inflammatory processes and is elevated in the retinas of glaucoma patients. Therefore, this study aimed to investigate the effects of the intravitreal injection of an anti-HMGB1 monoclonal antibody (anti-HMGB1 Ab) in an experimental animal model of glaucoma. Two groups of Spraque Dawley rats received episcleral vein occlusion to chronically elevate intraocular pressure (IOP): (1) the IgG group, intravitreal injection of an unspecific IgG as a control, n = 5, and (2) the HMGB1 group, intravitreal injection of an anti-HMGB1 Ab, n = 6. IOP, retinal nerve fiber layer thickness (RNFLT), and the retinal flash response were monitored longitudinally. Post-mortem examinations included immunohistochemistry, microarray, and mass spectrometric analysis. RNFLT was significantly increased in the HMGB1 group compared with the IgG group (p < 0.001). RGC density showed improved neuronal cell survival in the retina in HMGB1 compared with the IgG group (p < 0.01). Mass spectrometric proteomic analysis of retinal tissue showed an increased abundance of RNA metabolism-associated heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP U, D, and H2, in animals injected with the anti-HMGB1 Ab, indicating that the application of the antibody may cause increased gene expression. Microarray analysis showed a significantly decreased expression of C-X-C motif chemokine ligand 8 (CXCL8, p < 0.05) and connective tissue growth factor (CTGF, p < 0.01) in the HMGB1 group. Thus, these data suggest that intravitreal injection of anti-HMGB1 Ab reduced HMGB1-dependent inflammatory signaling and mediated RGC neuroprotection.
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19
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Siewe N, Friedman A. Combination therapy for mCRPC with immune checkpoint inhibitors, ADT and vaccine: A mathematical model. PLoS One 2022; 17:e0262453. [PMID: 35015785 PMCID: PMC8752026 DOI: 10.1371/journal.pone.0262453] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/23/2021] [Indexed: 11/27/2022] Open
Abstract
Metastatic castration resistant prostate cancer (mCRPC) is commonly treated by androgen deprivation therapy (ADT) in combination with chemotherapy. Immune therapy by checkpoint inhibitors, has become a powerful new tool in the treatment of melanoma and lung cancer, and it is currently being used in clinical trials in other cancers, including mCRPC. However, so far, clinical trials with PD-1 and CTLA-4 inhibitors have been disappointing. In the present paper we develop a mathematical model to assess the efficacy of any combination of ADT with cancer vaccine, PD-1 inhibitor, and CTLA-4 inhibitor. The model is represented by a system of partial differential equations (PDEs) for cells, cytokines and drugs whose density/concentration evolves in time within the tumor. Efficacy of treatment is determined by the reduction in tumor volume at the endpoint of treatment. In mice experiments with ADT and various combinations of PD-1 and CTLA-4 inhibitors, tumor volume at day 30 was always larger than the initial tumor. Our model, however, shows that we can decrease tumor volume with large enough dose; for example, with 10 fold increase in the dose of anti-PD-1, initial tumor volume will decrease by 60%. Although the treatment with ADT in combination with PD-1 inhibitor or CTLA-4 inhibitor has been disappointing in clinical trials, our simulations suggest that, disregarding negative effects, combinations of ADT with checkpoint inhibitors can be effective in reducing tumor volume if larger doses are used. This points to the need for determining the optimal combination and amounts of dose for individual patients.
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Affiliation(s)
- Nourridine Siewe
- School of Mathematical Sciences, College of Science, Rochester Institute of Technology, Rochester, New York, United States of America
| | - Avner Friedman
- Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
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20
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Reeves KM, Song PN, Angermeier A, Della Manna D, Li Y, Wang J, Yang ES, Sorace AG, Larimer BM. 18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition. Clin Cancer Res 2021; 28:327-337. [PMID: 34615724 DOI: 10.1158/1078-0432.ccr-21-2394] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/25/2021] [Accepted: 10/04/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of anti-tumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated. EXPERIMENTAL DESIGN In this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to non-invasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer. RESULTS Longitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (Ifng, Gzmb, and Tnf), damage-associated molecular pattern receptors (Tlr2/4) and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to non-responsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume. CONCLUSIONS The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
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Affiliation(s)
| | | | - Allyson Angermeier
- Cellular, Molecular, and Developmental Biology, University of Alabama at Birmingham
| | | | - Yufeng Li
- Division of Preventive Medicine, University of Alabama at Birmingham
| | - Jianbo Wang
- Cellular, Developmental and Integrative Biology, University of Alabama at Birmingham
| | - Eddy S Yang
- Department of Radiation Oncology, University of Alabama at Birmingham
| | - Anna G Sorace
- Radiology and Biomedical Engineering, University of Alabama at Birmingham
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21
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Boagni DA, Ravirala D, Zhang SX. Current strategies in engaging oncolytic viruses with antitumor immunity. Mol Ther Oncolytics 2021; 22:98-113. [PMID: 34514092 PMCID: PMC8411207 DOI: 10.1016/j.omto.2021.05.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Oncolytic virotherapy has produced promising yet limited results in preclinical and clinical studies. Besides direct oncolytic activity, a significant therapeutic mechanism of oncolytic virotherapy is the induction of tumor-specific immunity. Consequently, the efficacy of oncolytic viruses can be improved by the insertion of immune stimulator genes and rational combinatorial therapy with other immunotherapies. This article reviews recent efforts on arming oncolytic viruses with a variety of immune stimulator molecules, immune cell engagers, and other immune potentiating molecules. We outline what is known about the mechanisms of action and the corresponding results. The review also discusses recent preclinical and clinical studies of combining oncolytic virotherapy with immune-checkpoint inhibitors and the role of oncolytic virotherapy in changing the tumor microenvironment.
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Affiliation(s)
- Drew Ashton Boagni
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Divya Ravirala
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Shaun Xiaoliu Zhang
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
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22
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Yang H, Zeng Q, Silverman HA, Gunasekaran M, George SJ, Devarajan A, Addorisio ME, Li J, Tsaava T, Shah V, Billiar TR, Wang H, Brines M, Andersson U, Pavlov VA, Chang EH, Chavan SS, Tracey KJ. HMGB1 released from nociceptors mediates inflammation. Proc Natl Acad Sci U S A 2021; 118:e2102034118. [PMID: 34385304 PMCID: PMC8379951 DOI: 10.1073/pnas.2102034118] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Inflammation, the body's primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation. Because HMGB1 is an important inflammatory mediator that is synthesized by neurons, we reasoned nociceptor release of HMGB1 might be a component of the neuroinflammatory response. In support of this possibility, we show here that transgenic nociceptors expressing channelrhodopsin-2 (ChR2) directly release HMGB1 in response to light stimulation. Additionally, HMGB1 expression in neurons was silenced by crossing synapsin-Cre (Syn-Cre) mice with floxed HMGB1 mice (HMGB1f/f). When these mice undergo sciatic nerve injury to activate neurogenic inflammation, they are protected from the development of cutaneous inflammation and allodynia as compared to wild-type controls. Syn-Cre/HMGB1fl/fl mice subjected to experimental collagen antibody-induced arthritis, a disease model in which nociceptor-dependent inflammation plays a significant pathological role, are protected from the development of allodynia and joint inflammation. Thus, nociceptor HMGB1 is required to mediate pain and inflammation during sciatic nerve injury and collagen antibody-induced arthritis.
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Affiliation(s)
- Huan Yang
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030;
| | - Qiong Zeng
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Harold A Silverman
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Manojkumar Gunasekaran
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Sam J George
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Alex Devarajan
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Meghan E Addorisio
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Jianhua Li
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Téa Tsaava
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Vivek Shah
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213
| | - Haichao Wang
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Michael Brines
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Ulf Andersson
- Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Valentin A Pavlov
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
- The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030
- Donald and Barbara Zucker School of Medicine at Hofstra University, Hempstead, NY 11549
| | - Eric H Chang
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030
- The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030
- Donald and Barbara Zucker School of Medicine at Hofstra University, Hempstead, NY 11549
| | - Sangeeta S Chavan
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030;
- The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030
- Donald and Barbara Zucker School of Medicine at Hofstra University, Hempstead, NY 11549
| | - Kevin J Tracey
- Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030;
- The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030
- Donald and Barbara Zucker School of Medicine at Hofstra University, Hempstead, NY 11549
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23
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Pecci F, Cantini L, Bittoni A, Lenci E, Lupi A, Crocetti S, Giglio E, Giampieri R, Berardi R. Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer. Curr Treat Options Oncol 2021; 22:69. [PMID: 34110510 PMCID: PMC8192371 DOI: 10.1007/s11864-021-00870-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2021] [Indexed: 12/19/2022]
Abstract
Advanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An "immunoscore," based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.
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Affiliation(s)
- Federica Pecci
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Luca Cantini
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Alessandro Bittoni
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Edoardo Lenci
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Alessio Lupi
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Sonia Crocetti
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Enrica Giglio
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Riccardo Giampieri
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
| | - Rossana Berardi
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126 Ancona, Italy
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24
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Lu J, Yue Y, Xiong S. Extracellular HMGB1 augments macrophage inflammation by facilitating the endosomal accumulation of ALD-DNA via TLR2/4-mediated endocytosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166184. [PMID: 34087422 DOI: 10.1016/j.bbadis.2021.166184] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/13/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unclear pathogenesis. We previously reported that syngenetic, activated lymphocyte-derived DNA (ALD-DNA) could robustly elicit macrophage activation, which plays an important role in the pathogenesis of murine lupus nephritis. In addition, extracellular HMGB1 obviously facilitated the accumulation of ALD-DNA in endosomes and promoted macrophage inflammation. While the detailed mechanism was still unknown. In this study, we found that HMGB1 could obviously change the DNA uptake pathways in macrophages. ALD-DNA alone was mainly uptake by the low efficient and unselective macropinocytosis, while extracellular HMGB1 potently promoted the more efficient and specific clathrin-/caveolin-1-dependent receptor-mediated endocytosis pathways, and led to the rapid and abundant aggregation of ALD-DNA in endosomes. This effect relied on the DNA binding ability and TLR2/TLR4 of HMGB1. Our study not only helped us to understand the promotion mechanisms of extracellular HMGB1 on ALD-DNA-induced macrophage inflammation, but also provided some clues to the pathogenesis of SLE.
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Affiliation(s)
- Jincheng Lu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China
| | - Yan Yue
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China.
| | - Sidong Xiong
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China.
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25
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The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases. Cells 2021; 10:cells10051044. [PMID: 33925132 PMCID: PMC8145631 DOI: 10.3390/cells10051044] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/18/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.
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26
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Vaes RDW, Hendriks LEL, Vooijs M, De Ruysscher D. Biomarkers of Radiotherapy-Induced Immunogenic Cell Death. Cells 2021; 10:cells10040930. [PMID: 33920544 PMCID: PMC8073519 DOI: 10.3390/cells10040930] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/08/2021] [Accepted: 04/14/2021] [Indexed: 12/20/2022] Open
Abstract
Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.
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Affiliation(s)
- Rianne D. W. Vaes
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. 616, 6200 MD Maastricht, The Netherlands; (M.V.); (D.D.R.)
- Correspondence: ; Tel.: +31-(0)43-388-1585
| | - Lizza E. L. Hendriks
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. 616, 6200 MD Maastricht, The Netherlands;
| | - Marc Vooijs
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. 616, 6200 MD Maastricht, The Netherlands; (M.V.); (D.D.R.)
| | - Dirk De Ruysscher
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. 616, 6200 MD Maastricht, The Netherlands; (M.V.); (D.D.R.)
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27
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Goff PH, Zeng J, Rengan R, Schaub SK. Radiation and Modulation of the Tumor Immune Microenvironment in Non-Small Cell Lung Cancer. Semin Radiat Oncol 2021; 31:133-139. [PMID: 33610270 DOI: 10.1016/j.semradonc.2020.11.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Immune checkpoint inhibitors are approved for a variety of indications for locally advanced and metastatic non-small cell lung cancer (NSCLC), and trials are ongoing in the early-stage setting. There is an unmet need to understand which patients may derive benefit from immunotherapies and how to harness combined modality therapies to improve overall response rates and durability. Here, we review studies from the bench-to-bedside to examine the role of radiation therapy (RT) on the tumor immune microenvironment in NSCLC with an eye toward augmenting antitumor immunity. Together, these data provide a foundation for developing future clinical trials harnessing RT to augment antitumor immunity and highlight the need for correlative translational studies to directly characterize the impact of RT on the human NSCLC tumor immune microenvironment.
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Affiliation(s)
- Peter H Goff
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA.
| | - Jing Zeng
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA
| | - Ramesh Rengan
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA
| | - Stephanie K Schaub
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA
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28
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Hybrid micelles codelivering shikonin and IDO-1 siRNA enhance immunotherapy by remodeling immunosuppressive tumor microenvironment. Int J Pharm 2021; 597:120310. [PMID: 33540035 DOI: 10.1016/j.ijpharm.2021.120310] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/04/2021] [Accepted: 01/20/2021] [Indexed: 01/13/2023]
Abstract
Cancer immunotherapy is becoming an important option for malignant tumors treatment. Unfortunately, lacking intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive tumor microenvironment (ITM) remian primary barriers that immensely hamper its further clinical application. For boosting immune response and rebuilding the ITM, valid hybrid micelles (SK/siIDO1-HMs) delivering shikonin (SK) and IDO-1 knockdown siRNA (siIDO1) were conducted. SK/siIDO1-HMs had sufficient circulation time, favorable intratumoral accumulation and rapidly release in the cytoplasm. Importantly, SK was demonstrated to significantly elicit intratumoral accumulation of CTLs through inducing immunogenic cell death (ICD) of tumor cells. Moreover, siIDO1 downregulated the IDO-1-caused immunosuppression and restrained regulatory T lymphocytes (Tregs). In summary, SK/siIDO1-HMs displayed a remarkable potential for tumor therapy via triggering the ICD and moderating the IDO-1-triggered immunosuppression.
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29
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Mohamed H, Clemen R, Freund E, Lackmann JW, Wende K, Connors J, Haddad EK, Dampier W, Wigdahl B, Miller V, Bekeschus S, Krebs FC. Non-thermal plasma modulates cellular markers associated with immunogenicity in a model of latent HIV-1 infection. PLoS One 2021; 16:e0247125. [PMID: 33647028 PMCID: PMC7920340 DOI: 10.1371/journal.pone.0247125] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/02/2021] [Indexed: 12/25/2022] Open
Abstract
Effective control of infection by human immunodeficiency virus type 1 (HIV-1), the causative agent of the acquired immunodeficiency syndrome (AIDS), requires continuous and life-long use of anti-retroviral therapy (ART) by people living with HIV-1 (PLWH). In the absence of ART, HIV-1 reemergence from latently infected cells is ineffectively suppressed due to suboptimal innate and cytotoxic T lymphocyte responses. However, ART-free control of HIV-1 infection may be possible if the inherent immunological deficiencies can be reversed or restored. Herein we present a novel approach for modulating the immune response to HIV-1 that involves the use of non-thermal plasma (NTP), which is an ionized gas containing various reactive oxygen and nitrogen species (RONS). J-Lat cells were used as a model of latent HIV-1 infection to assess the effects of NTP application on viral latency and the expression of pro-phagocytic and pro-chemotactic damage-associated molecular patterns (DAMPs). Exposure of J-Lat cells to NTP resulted in stimulation of HIV-1 gene expression, indicating a role in latency reversal, a necessary first step in inducing adaptive immune responses to viral antigens. This was accompanied by the release of pro-inflammatory cytokines and chemokines including interleukin-1β (IL-1β) and interferon-γ (IFN-γ); the display of pro-phagocytic markers calreticulin (CRT), heat shock proteins (HSP) 70 and 90; and a correlated increase in macrophage phagocytosis of NTP-exposed J-Lat cells. In addition, modulation of surface molecules that promote or inhibit antigen presentation was also observed, along with an altered array of displayed peptides on MHC I, further suggesting methods by which NTP may modify recognition and targeting of cells in latent HIV-1 infection. These studies represent early progress toward an effective NTP-based ex vivo immunotherapy to resolve the dysfunctions of the immune system that enable HIV-1 persistence in PLWH.
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Affiliation(s)
- Hager Mohamed
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Ramona Clemen
- Centre for Innovation Competence (ZIK) plasmatis, Leibniz Institute for Plasma Science and Technology Greifswald (INP), Greifswald, Germany
| | - Eric Freund
- Centre for Innovation Competence (ZIK) plasmatis, Leibniz Institute for Plasma Science and Technology Greifswald (INP), Greifswald, Germany
| | - Jan-Wilm Lackmann
- Centre for Innovation Competence (ZIK) plasmatis, Leibniz Institute for Plasma Science and Technology Greifswald (INP), Greifswald, Germany.,CECAD proteomics facility, University of Cologne, Cologne, Germany
| | - Kristian Wende
- Centre for Innovation Competence (ZIK) plasmatis, Leibniz Institute for Plasma Science and Technology Greifswald (INP), Greifswald, Germany
| | - Jennifer Connors
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Elias K Haddad
- Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Will Dampier
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Brian Wigdahl
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Vandana Miller
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Sander Bekeschus
- Centre for Innovation Competence (ZIK) plasmatis, Leibniz Institute for Plasma Science and Technology Greifswald (INP), Greifswald, Germany
| | - Fred C Krebs
- Department of Microbiology and Immunology, Institute for Molecular Medicine & Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
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30
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Sacco A, Battaglia AM, Botta C, Aversa I, Mancuso S, Costanzo F, Biamonte F. Iron Metabolism in the Tumor Microenvironment-Implications for Anti-Cancer Immune Response. Cells 2021; 10:303. [PMID: 33540645 PMCID: PMC7913036 DOI: 10.3390/cells10020303] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: i) the "hot" tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and ii) the "cold" tumors, which are often very poor in immune cells, mainly due to immune exclusion.
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Affiliation(s)
- Alessandro Sacco
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
| | - Anna Martina Battaglia
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
| | | | - Ilenia Aversa
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
| | - Serafina Mancuso
- U.O. Biochimica Clinica, Azienda Ospedaliero Universitaria Mater Domini, 88100 Catanzaro, Italy;
| | - Francesco Costanzo
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
- Center of Interdepartmental Services (CIS), “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy
| | - Flavia Biamonte
- Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy; (A.S.); (A.M.B.); (I.A.); (F.C.)
- Center of Interdepartmental Services (CIS), “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy
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31
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de Souza ASC, Gonçalves LB, Lepique AP, de Araujo-Souza PS. The Role of Autophagy in Tumor Immunology-Complex Mechanisms That May Be Explored Therapeutically. Front Oncol 2020; 10:603661. [PMID: 33335860 PMCID: PMC7736605 DOI: 10.3389/fonc.2020.603661] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/02/2020] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment (TME) is complex, and its composition and dynamics determine tumor fate. From tumor cells themselves, with their capacity for unlimited replication, migration, and invasion, to fibroblasts, endothelial cells, and immune cells, which can have pro and/or anti-tumor potential, interaction among these elements determines tumor progression. The understanding of molecular pathways involved in immune escape has permitted the development of cancer immunotherapies. Targeting molecules or biological processes that inhibit antitumor immune responses has allowed a significant improvement in cancer patient’s prognosis. Autophagy is a cellular process required to eliminate dysfunctional proteins and organelles, maintaining cellular homeostasis. Usually a process associated with protection against cancer, autophagy associated to cancer cells has been reported in response to hypoxia, nutrient deficiency, and oxidative stress, conditions frequently observed in the TME. Recent studies have shown a paradoxical association between autophagy and tumor immune responses. Tumor cell autophagy increases the expression of inhibitory molecules, such as PD-1 and CTLA-4, which block antitumor cytotoxic responses. Moreover, it can also directly affect antitumor immune responses by, for example, degrading NK cell-derived granzyme B and protecting tumor cells. Interestingly, the activation of autophagy on dendritic cells has the opposite effects, enhancing antigen presentation, triggering CD8+ T cells cytotoxic activity, and reducing tumor growth. Therefore, this review will focus on the most recent aspects of autophagy and tumor immune environment. We describe the dual role of autophagy in modulating tumor immune responses and discuss some aspects that must be considered to improve cancer treatment.
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Affiliation(s)
- Alana Serrano Campelo de Souza
- Laboratório de Imunogenética e Histocompatibilidade (LIGH), Departamento de Genética, Setor de Ciências Biológicas, Universidade Federal do Paraná (UFPR), Curitiba, Brazil.,Programa de Pós-graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Letícia Boslooper Gonçalves
- Laboratório de Imunogenética e Histocompatibilidade (LIGH), Departamento de Genética, Setor de Ciências Biológicas, Universidade Federal do Paraná (UFPR), Curitiba, Brazil.,Programa de Pós-graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
| | - Ana Paula Lepique
- Laboratório de Imunomodulação, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Patrícia Savio de Araujo-Souza
- Laboratório de Imunogenética e Histocompatibilidade (LIGH), Departamento de Genética, Setor de Ciências Biológicas, Universidade Federal do Paraná (UFPR), Curitiba, Brazil
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32
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Montero L, Cervantes-Torres J, Sciutto E, Fragoso G. Helminth-derived peptide GK-1 induces Myd88-dependent pro-inflammatory signaling events in bone marrow-derived antigen-presenting cells. Mol Immunol 2020; 128:22-32. [PMID: 33049560 DOI: 10.1016/j.molimm.2020.09.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 09/19/2020] [Accepted: 09/21/2020] [Indexed: 12/17/2022]
Abstract
GK-1 is an immunomodulatory, 18-aa-long peptide that has been proved to promote the activation of mouse peritoneal macrophages and LPS-pulsed mouse bone marrow-derived dendritic cells (BM-DCs). This study is aimed to explore the mechanisms underlying the activation of these antigen-presenting cells (APCs) by GK-1. In our study, GK-1 up-regulated in vitro the expression of CD86 and CD40, and it increased the secretion of NO in bone marrow-derived macrophages (BMDMs). In BM-DCs, GK-1 upregulated the expression of MHC class II and CD86. Additionally, GK-1 was found to be involved in the phosphorylation of MAPK p38, JNK and ERK 1/2 and in Myd88-dependent activation of NF-κB in both antigen-presenting cell types. In vivo, GK-1 increased the secretion of IL-15, CCL2, and IL-6 through a Myd88-dependent mechanism. This study demonstrated that GK-1 promotes the activation and effector activity of APCs through a mechanism dependent on Myd88, probably involving a Toll-like receptor as a target.
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Affiliation(s)
- Laura Montero
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, 04510, Mexico.
| | | | - Edda Sciutto
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, 04510, Mexico.
| | - Gladis Fragoso
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, 04510, Mexico.
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Yazdani Z, Rafiei A, Yazdani M, Valadan R. Design an Efficient Multi-Epitope Peptide Vaccine Candidate Against SARS-CoV-2: An in silico Analysis. Infect Drug Resist 2020; 13:3007-3022. [PMID: 32943888 PMCID: PMC7459237 DOI: 10.2147/idr.s264573] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To date, no specific vaccine or drug has been proven to be effective against SARS-CoV-2 infection. Therefore, we implemented an immunoinformatic approach to design an efficient multi-epitopes vaccine against SARS-CoV-2. RESULTS The designed-vaccine construct consists of several immunodominant epitopes from structural proteins of spike, nucleocapsid, membrane, and envelope. These peptides promote cellular and humoral immunity and interferon-gamma responses. Also, these epitopes have a high antigenic capacity and are not likely to cause allergies. To enhance the vaccine immunogenicity, we used three potent adjuvants: Flagellin of Salmonella enterica subsp. enterica serovar Dublin, a driven peptide from high mobility group box 1 as HP-91, and human beta-defensin 3 protein. The physicochemical and immunological properties of the vaccine structure were evaluated. The tertiary structure of the vaccine protein was predicted and refined by Phyre2 and Galaxi refine and validated using RAMPAGE and ERRAT. Results of ElliPro showed 246 sresidues from vaccine might be conformational B-cell epitopes. Docking of the vaccine with toll-like receptors (TLR) 3, 5, 8, and angiotensin-converting enzyme 2 approved an appropriate interaction between the vaccine and receptors. Prediction of mRNA secondary structure and in silico cloning demonstrated that the vaccine can be efficiently expressed in Escherichia coli. CONCLUSION Our results demonstrated that the multi-epitope vaccine might be potentially antigenic and induce humoral and cellular immune responses against SARS-CoV-2. This vaccine can interact appropriately with the TLR3, 5, and 8. Also, it has a high-quality structure and suitable characteristics such as high stability and potential for expression in Escherichia coli .
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Affiliation(s)
- Zahra Yazdani
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Alireza Rafiei
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammadreza Yazdani
- Department of Chemistry, Isfahan University of Technology, Isfahan84156-83111, Iran
| | - Reza Valadan
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Gao J, Wang WQ, Pei Q, Lord MS, Yu HJ. Engineering nanomedicines through boosting immunogenic cell death for improved cancer immunotherapy. Acta Pharmacol Sin 2020; 41:986-994. [PMID: 32317755 PMCID: PMC7470797 DOI: 10.1038/s41401-020-0400-z] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 03/16/2020] [Indexed: 02/06/2023]
Abstract
Current cancer immunotherapy has limited response rates in a large variety of solid tumors partly due to the low immunogenicity of the tumor cells and the immunosuppressive tumor microenvironment (ITM). A number of clinical cancer treatment modalities, including radiotherapy, chemotherapy, photothermal and photodynamic therapy, have been shown to elicit immunogenicity by inducing immunogenic cell death (ICD). However, ICD-based immunotherapy is restricted by the ITM limiting its efficacy in eliciting a long-term antitumor immune response, and by severe systemic toxicity. To address these challenges, nanomedicine-based drug delivery strategies have been exploited for improving cancer immunotherapy by boosting ICD of the tumor cells. Nanosized drug delivery systems are promising for increasing drug accumulation at the tumor site and codelivering ICD inducers and immune inhibitors to simultaneously elicit the immune response and relieve the ITM. This review highlights the recent advances in nanomedicine-based immunotherapy utilizing ICD-based approaches. A perspective on the clinical translation of nanomedicine-based cancer immunotherapy is also provided.
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Affiliation(s)
- Jing Gao
- Key Laboratory of Drug Research & Centre of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Peking University Shenzhen Institute, Shenzhen, 518055, China
| | - Wei-Qi Wang
- Key Laboratory of Drug Research & Centre of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Pharmacy, Nantong University, Nantong, 226001, China
| | - Qing Pei
- Key Laboratory of Drug Research & Centre of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Megan S Lord
- Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Hai-Jun Yu
- Key Laboratory of Drug Research & Centre of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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Milani A, Baesi K, Agi E, Bolhassani A. Detection of Anti-IgGs against Heat Shock Proteins 27 and 20, HP91 Peptide, and HIV-1 Polypeptides in HIV-Positive and Negative Patients. JOURNAL OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES 2020. [DOI: 10.29252/jommid.8.3.113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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He C, Huang X, Zhang Y, Lin X, Li S. T-cell activation and immune memory enhancement induced by irreversible electroporation in pancreatic cancer. Clin Transl Med 2020; 10:e39. [PMID: 32508058 PMCID: PMC7403705 DOI: 10.1002/ctm2.39] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 04/26/2020] [Accepted: 04/27/2020] [Indexed: 12/16/2022] Open
Abstract
Background Irreversible electroporation is shown to induce immune changes in pancreatic cancer while the histology evidences are still lacking. The aim of this study is to show the immune changes in histology and explore whether irreversible electroporation (IRE) can induce immunogenic cell death (ICD) of tumor cells and activate specific immune responses. Methods Subcutaneous and orthotopic pancreatic cancer models were established and used to evaluate the effect of immune modulation of IRE. The infiltration of T cells was assessed in several tissue samples before and after IRE. Abscopal effect was then assessed by comparing the tumor growth of subcutaneous tumors after in situ ablation with IRE or exposure to tumor culture supernatant (TSN) of IRE‐treated Pan02. The expression of damage‐associated molecular patterns (DAMPs) of tumor cells after IRE was detected in vitro. Results IRE could significantly suppress the tumor growth and increase the infiltration of CD8+ T cells. After ablation with IRE or stimulation with TSN of Pan02 treated by IRE, the growth of untreated tumor was suppressed and the effector CD8+ T cells and memory T cells increased significantly in mice. Additionally, the inhibition effect of tumor growth increased along with the increasing strength levels of electroporation. IRE induced ICD of tumor cells by increasing the synthesis and secretion of DAMPs. Conclusions IRE induced local immunomodulation by increasing specific T cells infiltration. Through enhancing specific immune memory, IRE not only led a complete tumor regression in suit, but also induced abscopal effect, suppressing the growth of the latent lesions.
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Affiliation(s)
- Chaobin He
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Xin Huang
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Yu Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiaojun Lin
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Shengping Li
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
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Bemani P, Amirghofran Z, Mohammadi M. Designing a multi-epitope vaccine against blood-stage of Plasmodium falciparum by in silico approaches. J Mol Graph Model 2020; 99:107645. [PMID: 32454399 DOI: 10.1016/j.jmgm.2020.107645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 12/11/2022]
Abstract
Plasmodium falciparum causes the most severe form of malaria disease and is the major cause of infection-related mortalities in the world. Due to increasing in P. falciparum resistance to the first-line antimalarial drugs, an effective vaccine for the control and elimination of malaria infection is urgent. Because the pathogenesis of malaria disease results from blood-stage infection, and all of the symptoms and clinical illness of malaria occur during this stage, there is a strong rationale to develop vaccine against this stage. In the present study, different structural-vaccinology and immuno informatics tools were applied to design an effective antibody-inducing multi-epitope vaccine against the blood-stage of P. falciparum. The designed multi-epitope vaccine was composed of three main parts including B cell epitopes, T helper (Th) cell epitopes, and two adjuvant motives (HP91 and RS09), which were linked to each other via proper linkers. B cell and T cell epitopes were derived from four protective antigens expressed on the surface of merozoites, which are critical to invade the erythrocytes. HP91 and RS09 adjuvants and Th cell epitopes were used to induce, enhance and direct the best form of humoral immune-response against P. falciparum surface merozoite antigens. The vaccine construct was modeled, and after model quality evaluation and refinement by different software, the high-quality 3D-structure model of the vaccine was achieved. Analysis of immunological and physicochemical features of the vaccine showed acceptable results. We believe that this multi-epitope vaccine can be effective for preventing malaria disease caused by P. falciparum.
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Affiliation(s)
- Peyman Bemani
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Zahra Amirghofran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mozafar Mohammadi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Asadzadeh Z, Safarzadeh E, Safaei S, Baradaran A, Mohammadi A, Hajiasgharzadeh K, Derakhshani A, Argentiero A, Silvestris N, Baradaran B. Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death. Cancers (Basel) 2020; 12:E1047. [PMID: 32340275 PMCID: PMC7226590 DOI: 10.3390/cancers12041047] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/08/2020] [Accepted: 04/17/2020] [Indexed: 12/31/2022] Open
Abstract
Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.
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Affiliation(s)
- Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (Z.A.); (S.S.); (K.H.); (A.D.)
| | - Elham Safarzadeh
- Department of Immunology and Microbiology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil 5618985991, Iran;
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (Z.A.); (S.S.); (K.H.); (A.D.)
| | - Ali Baradaran
- Research & Development Lab, BSD Robotics, 4500 Brisbane, Australia;
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark;
| | - Khalil Hajiasgharzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (Z.A.); (S.S.); (K.H.); (A.D.)
| | - Afshin Derakhshani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (Z.A.); (S.S.); (K.H.); (A.D.)
| | | | - Nicola Silvestris
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy;
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran; (Z.A.); (S.S.); (K.H.); (A.D.)
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
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Lai X, Hao W, Friedman A. TNF-α inhibitor reduces drug-resistance to anti-PD-1: A mathematical model. PLoS One 2020; 15:e0231499. [PMID: 32310956 PMCID: PMC7170257 DOI: 10.1371/journal.pone.0231499] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 03/24/2020] [Indexed: 01/05/2023] Open
Abstract
Drug resistance is a primary obstacle in cancer treatment. In many patients who at first respond well to treatment, relapse occurs later on. Various mechanisms have been explored to explain drug resistance in specific cancers and for specific drugs. In this paper, we consider resistance to anti-PD-1, a drug that enhances the activity of anti-cancer T cells. Based on results in experimental melanoma, it is shown, by a mathematical model, that resistances to anti-PD-1 can be significantly reduced by combining it with anti-TNF-α. The model is used to simulate the efficacy of the combined therapy with different range of doses, different initial tumor volume, and different schedules. In particular, it is shown that under a course of treatment with 3-week cycles where each drug is injected in the first day of either week 1 or week 2, injecting anti-TNF-α one week after anti-PD-1 is the most effective schedule in reducing tumor volume.
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Affiliation(s)
- Xiulan Lai
- Institute for Mathematical Sciences, Renmin University of China, Beijing, P. R. China
| | - Wenrui Hao
- Department of Mathematics, Pennsylvania State University, State College, PA, United States of America
| | - Avner Friedman
- Mathematical Bioscience Institute & Department of Mathematics, Ohio State University, Columbus, OH, United States of America
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Serrano-Del Valle A, Naval J, Anel A, Marzo I. Novel Forms of Immunomodulation for Cancer Therapy. Trends Cancer 2020; 6:518-532. [PMID: 32460005 DOI: 10.1016/j.trecan.2020.02.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/07/2020] [Accepted: 02/19/2020] [Indexed: 02/07/2023]
Abstract
In recent years immunotherapy has provided new hope for cancer patients. However, some patients eventually relapse. Immunological responses are thought to underlie the long-term effects of conventional or targeted therapies. Whether this influence emerges from direct effects on cancer cells through immunogenic cell death (ICD) or by modulating the immune environment requires further clarification. ICD-related molecular mechanisms are also shared by cell-intrinsic defense responses that combat foreign intrusions. Indeed, we could potentially mimic and harness these processes to improve cancer immunogenicity. In addition, the microbiome is materializing as a missing factor in the cancer-immune therapy axis. The emerging idea of manipulating the gut microbiota to improve responses to anticancer therapy is becoming increasingly popular, but further clinical authentication is needed.
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Affiliation(s)
- Alfonso Serrano-Del Valle
- Apoptosis, Immunity, and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, and Aragon Health Research Institute (IIS-Aragon), Zaragoza 50009, Spain.
| | - Javier Naval
- Apoptosis, Immunity, and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, and Aragon Health Research Institute (IIS-Aragon), Zaragoza 50009, Spain
| | - Alberto Anel
- Apoptosis, Immunity, and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, and Aragon Health Research Institute (IIS-Aragon), Zaragoza 50009, Spain
| | - Isabel Marzo
- Apoptosis, Immunity, and Cancer Group, Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, and Aragon Health Research Institute (IIS-Aragon), Zaragoza 50009, Spain
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Wang LX, Zhu XM, Luo YN, Wu Y, Dong N, Tong YL, Yao YM. Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein. Cell Death Dis 2020; 11:125. [PMID: 32071292 PMCID: PMC7028717 DOI: 10.1038/s41419-020-2324-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 12/15/2022]
Abstract
Sestrin2 (SESN2) is a highly evolutionary conserved protein and involved in different cellular responses to various stresses. However, the potential function of SESN2 in immune system remains unclear. The present study was designed to test whether dendritic cells (DCs) could express SESN2, and investigate the underlying molecular mechanism as well as its potential significance. Herein, we firstly reported that SESN2 was expressed in DCs after high mobility group box-1 protein (HMGB1) stimulation and the apoptosis of DCs was obviously increased when SESN2 gene silenced by siRNA. Cells undergone SESN2-knockdown promoted endoplasmic reticulum (ER) stress (ERS)-related cell death, markedly exacerbated ER disruption as well as the formation of dilated and aggregated structures, and they significantly aggravated the extent of ERS response. Conversely, overexpressing SESN2 DCs markedly decreased apoptotic rates and attenuated HMGB1-induced ER morphology fragment together with inhibition of ERS-related protein translation. Furthermore, sesn2−/−-deficient mice manifested increased DC apoptosis and aggravated ERS extent in septic model. These results indicate that SESN2 appears to be a potential regulator to inhibit apoptotic ERS signaling that exerts a protective effect on apoptosis of DCs in the setting of septic challenge.
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Affiliation(s)
- Li-Xue Wang
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, PR China.,First Medical Center of the Chinese PLA General Hospital, Beijing, 100853, PR China
| | - Xiao-Mei Zhu
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, PR China
| | - Yi-Nan Luo
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, PR China
| | - Yao Wu
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, PR China
| | - Ning Dong
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, PR China
| | - Ya-Lin Tong
- Department of Burns and Plastic Surgery, 924th Hospital of Chinese PLA, Guilin, 541002, PR China
| | - Yong-Ming Yao
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, PR China. .,First Medical Center of the Chinese PLA General Hospital, Beijing, 100853, PR China. .,State Key Laboratory of Kidney Disease, the Chinese PLA General Hospital, Beijing, 100853, PR China.
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Trovato R, Canè S, Petrova V, Sartoris S, Ugel S, De Sanctis F. The Engagement Between MDSCs and Metastases: Partners in Crime. Front Oncol 2020; 10:165. [PMID: 32133298 PMCID: PMC7040035 DOI: 10.3389/fonc.2020.00165] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 01/30/2020] [Indexed: 12/18/2022] Open
Abstract
Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed “pre-metastatic niche” (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically re-program not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an “emergency” myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease.
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Affiliation(s)
- Rosalinda Trovato
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Stefania Canè
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Varvara Petrova
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Silvia Sartoris
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Stefano Ugel
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
| | - Francesco De Sanctis
- Section of Immunology, Department of Medicine, University of Verona, Verona, Italy
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Yamanaka Y, Sawai Y, Nomura S. Platelet-Derived Microparticles are an Important Biomarker in Patients with Cancer-Associated Thrombosis. Int J Gen Med 2019; 12:491-497. [PMID: 32099444 PMCID: PMC6997194 DOI: 10.2147/ijgm.s236166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022] Open
Abstract
Background Platelet-derived microparticles (PDMPs) that ultimately cause vascular complications might be used as a tool to assess thrombotic areas. We identified PDMPs, high-mobility group box-1 (HMGB1) and soluble endothelial protein C receptor (sEPCR) as useful prognosis indicators for cancer-related thrombosis (CAT) to evaluate the utility of PDMPs in cancer patients. Methods We investigated 232 cancer patients: 24 (10.3%) had thrombotic complications within 6 months after their first examination. Levels of PDMP and biomarkers were measured by enzyme-linked immunosorbent assay. Results The levels of PDMPs, HMGB1 and sEPCR were higher in cancer patients compared with controls. In particular, these levels were significantly elevated in lung cancer patients compared with controls, and all were higher in CAT-positive patients compared with CAT-negative patients. In particular, PDMP levels in CAT-positive patients were significantly elevated compared with CAT-negative patients. PDMP levels were significantly lower in patients who lived for more than 901 days after their first examination compared with previous data. PDMP levels were positively correlated with HMGB1, and caused the dose-dependent elevation of PDMPs in vitro using platelet-rich plasma from healthy persons. Conclusion The combined increase in PDMP and HMGB1 levels might be related to CAT in cancer patients. Therefore, coagulatory dysfunction may result from increased levels of these biomarkers and contribute to the poor prognosis of cancer patients.
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Affiliation(s)
- Yuta Yamanaka
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Yusuke Sawai
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
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Zhang YG, Zhu X, Lu R, Messer JS, Xia Y, Chang EB, Sun J. Intestinal epithelial HMGB1 inhibits bacterial infection via STAT3 regulation of autophagy. Autophagy 2019; 15:1935-1953. [PMID: 30894054 PMCID: PMC6844505 DOI: 10.1080/15548627.2019.1596485] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 02/20/2019] [Accepted: 03/01/2019] [Indexed: 12/30/2022] Open
Abstract
Extracellular HMGB1 (high mobility group box 1) is considered as a damage-associated molecular pattern protein. However, little is known about its intracellular role. We studied the mechanism whereby intestinal epithelial HMGB1 contributes to host defense, using cell culture, colonoids, conditional intestinal epithelial HMGB1-knockout mice with Salmonella-colitis, il10-/- mice, and human samples. We report that intestinal HMGB1 is an important contributor to host protection from inflammation and infection. We identified a physical interaction between HMGB1 and STAT3. Lacking intestinal epithelial HMGB1 led to redistribution of STAT3 and activation of STAT3 post bacterial infection. Indeed, Salmonella-infected HMGB1-deficient cells exhibited less macroautophagy/autophagy due to decreased expression of autophagy proteins and transcriptional repression by activated STAT3. Then, increased p-STAT3 and extranuclear STAT3 reduced autophagic responses and increased inflammation. STAT3 inhibition restored autophagic responses and reduced bacterial invasion in vitro and in vivo. Moreover, low level of HMGB1 was correlated with reduced nuclear STAT3 and enhanced p-STAT3 in inflamed intestine of il10-/- mice and inflammatory bowel disease (IBD) patients. We revealed that colonic epithelial HMGB1 was directly involved in the suppression of STAT3 activation and the protection of intestine from bacterial infection and injury. Abbreviations: ATG16L1: autophagy-related 16-like 1 (S. cerevisiae); DAMP: damage-associated molecular pattern; HBSS: Hanks balanced salt solution; HMGB1: high mobility group box 1; IBD: inflammatory bowel disease; IL1B/Il-1β: interleukin 1 beta; IL10: interleukin 10; IL17/IL-17: interleukin 17; MEFs: mouse embryonic fibroblasts; STAT3: signal transducer and activator of transcription 3; TLR: toll-like receptor; TNF/TNF-α: tumor necrosis factor.
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Affiliation(s)
- Yong-Guo Zhang
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiaorong Zhu
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Rong Lu
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Jeannette S. Messer
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Yinglin Xia
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Eugene B. Chang
- Department of Medicine, Knapp Center for Biomedical Discovery, University of Chicago, Chicago, IL, USA
| | - Jun Sun
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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Jiraviriyakul A, Songjang W, Kaewthet P, Tanawatkitichai P, Bayan P, Pongcharoen S. Honokiol-enhanced cytotoxic T lymphocyte activity against cholangiocarcinoma cells mediated by dendritic cells pulsed with damage-associated molecular patterns. World J Gastroenterol 2019; 25:3941-3955. [PMID: 31413529 PMCID: PMC6689815 DOI: 10.3748/wjg.v25.i29.3941] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/21/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma or biliary tract cancer has a high mortality rate resulting from late presentation and ineffective treatment strategy. Since immunotherapy by dendritic cells (DC) may be beneficial for cholangiocarcinoma treatment but their efficacy against cholangiocarcinoma was low. We suggest how such anti-tumor activity can be increased using cell lysates derived from an honokiol-treated cholangiocarcinoma cell line (KKU-213L5). AIM To increase antitumour activity of DCs pulsed with cell lysates derived from honokiol-treated cholangiocarcinoma cell line (KKU-213L5). METHODS The effect of honokiol, a phenolic compound isolated from Magnolia officinalis, on choangiocarcinoma cells was investigated in terms of the cytotoxicity and the expression of damage-associated molecular patterns (DAMPs). DCs were loaded with tumour cell lysates derived from honokiol-treated cholangiocarcinoma cells their efficacy including induction of T lymphocyte proliferation, proinflammatory cytokine production and cytotoxicity effect on target cholangiocarcinoma cells were evaluated. RESULTS Honokiol can effectively activate cholangiocarcinoma apoptosis and increase the release of damage-associated molecular patterns. DCs loaded with cell lysates derived from honokiol-treated tumour cells enhanced priming and stimulated T lymphocyte proliferation and type I cytokine production. T lymphocytes stimulated with DCs pulsed with cell lysates of honokiol-treated tumour cells significantly increased specific killing of human cholangiocarcinoma cells compared to those associated with DCs pulsed with cell lysates of untreated cholangiocarcinoma cells. CONCLUSION The present findings suggested that honokiol was able to enhance the immunogenicity of cholangiocarcinoma cells associated with increased effectiveness of DC-based vaccine formulation. Treatment of tumour cells with honokiol offers a promising approach as an ex vivo DC-based anticancer vaccine.
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Affiliation(s)
- Arunya Jiraviriyakul
- Biomedical Science Graduate School, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Worawat Songjang
- Biomedical Science Graduate School, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Pongsathorn Kaewthet
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Phachsita Tanawatkitichai
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Punyapat Bayan
- Department of Medical technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sutatip Pongcharoen
- Biomedical Science Graduate School, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
- Research Centre of Academic Excellence in Petroleum, Petrochemical, and Advanced Materials, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand
- Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
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Serrano-Del Valle A, Anel A, Naval J, Marzo I. Immunogenic Cell Death and Immunotherapy of Multiple Myeloma. Front Cell Dev Biol 2019; 7:50. [PMID: 31041312 PMCID: PMC6476910 DOI: 10.3389/fcell.2019.00050] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/19/2019] [Indexed: 12/24/2022] Open
Abstract
Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of “immunogenic cell death” (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.
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Affiliation(s)
| | - Alberto Anel
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain
| | - Javier Naval
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain
| | - Isabel Marzo
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain
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Yang H, Liu H, Zeng Q, Imperato GH, Addorisio ME, Li J, He M, Cheng KF, Al-Abed Y, Harris HE, Chavan SS, Andersson U, Tracey KJ. Inhibition of HMGB1/RAGE-mediated endocytosis by HMGB1 antagonist box A, anti-HMGB1 antibodies, and cholinergic agonists suppresses inflammation. Mol Med 2019; 25:13. [PMID: 30975096 PMCID: PMC6460792 DOI: 10.1186/s10020-019-0081-6] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/21/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Extracellular high mobility group box 1 protein (HMGB1) serves a central role in inflammation as a transporter protein, which binds other immune-activating molecules that are endocytosed via the receptor for advanced glycation end-products (RAGE). These pro-inflammatory complexes are targeted to the endolysosomal compartment, where HMGB1 permeabilizes the lysosomes. This enables HMGB1-partner molecules to avoid degradation, to leak into the cytosol, and to reach cognate immune-activating sensors. Lipopolysaccharide (LPS) requires this pathway to generate pyroptosis by accessing its key cytosolic receptors, murine caspase 11, or the human caspases 4 and 5. This lytic, pro-inflammatory cell death plays a fundamental pathogenic role in gram-negative sepsis. The aim of the study was to identify molecules inhibiting HMGB1 or HMGB1/LPS cellular internalization. METHODS Endocytosis was studied in cultured macrophages using Alexa Fluor-labeled HMGB1 or complexes of HMGB1 and Alexa Fluor-labeled LPS in the presence of an anti-HMGB1 monoclonal antibody (mAb), recombinant HMGB1 box A protein, acetylcholine, the nicotinic acetylcholine receptor subtype alpha 7 (α7 nAChR) agonist GTS-21, or a dynamin-specific inhibitor of endocytosis. Images were obtained by fluorescence microscopy and quantified by the ImageJ processing program (NIH). Data were analyzed using student's t test or one-way ANOVA followed by the least significant difference or Tukey's tests. RESULTS Anti-HMGB1 mAb, recombinant HMGB1 antagonist box A protein, acetylcholine, GTS-21, and the dynamin-specific inhibitor of endocytosis inhibited internalization of HMGB1 or HMGB1-LPS complexes in cultured macrophages. These agents prevented macrophage activation in response to HMGB1 and/or HMGB1-LPS complexes. CONCLUSION These results demonstrate that therapies based on HMGB1 antagonists and the cholinergic anti-inflammatory pathway share a previously unrecognized molecular mechanism of substantial clinical relevance.
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Affiliation(s)
- Huan Yang
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Hui Liu
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Qiong Zeng
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Gavin H. Imperato
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Meghan E. Addorisio
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Jianhua Li
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Mingzhu He
- Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Kai Fan Cheng
- Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Yousef Al-Abed
- Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
- Elmezzi Graduate School of Molecular Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
- Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
| | - Helena E. Harris
- Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden
| | - Sangeeta S. Chavan
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
- Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
- Elmezzi Graduate School of Molecular Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Ulf Andersson
- Department of Women’s and Children’s Health, Karolinska Institute, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Kevin J. Tracey
- Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
- Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
- Elmezzi Graduate School of Molecular Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
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Lai X, Friedman A. How to schedule VEGF and PD-1 inhibitors in combination cancer therapy? BMC SYSTEMS BIOLOGY 2019; 13:30. [PMID: 30894166 PMCID: PMC6427900 DOI: 10.1186/s12918-019-0706-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 02/19/2019] [Indexed: 11/23/2022]
Abstract
BACKGROUND One of the questions in the design of cancer clinical trials with combination of two drugs is in which order to administer the drugs. This is an important question, especially in the case where one agent may interfere with the effectiveness of the other agent. RESULTS In the present paper we develop a mathematical model to address this scheduling question in a specific case where one of the drugs is anti-VEGF, which is known to affect the perfusion of other drugs. As a second drug we take anti-PD-1. Both drugs are known to increase the activation of anticancer T cells. Our simulations show that in the case where anti-VEGF reduces the perfusion, a non-overlapping schedule is significantly more effective than a simultaneous injection of the two drugs, and it is somewhat more beneficial to inject anti-PD-1 first. CONCLUSION The method and results of the paper can be extended to other combinations, and they could play an important role in the design of clinical trials with combination therapy, where scheduling strategies may significantly affect the outcome.
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Affiliation(s)
- Xiulan Lai
- Institute for Mathematical Sciences, Renmin University of China, Beijing, People’s Republic of China
| | - Avner Friedman
- Mathematical Bioscience Institute & Department of Mathematics, Ohio State University, Columbus, OH USA
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Ramezani A, Aghakhani A, Soleymani S, Bavand A, Bolhassani A. Significance of serum antibodies against HPV E7, Hsp27, Hsp20 and Hp91 in Iranian HPV-exposed women. BMC Infect Dis 2019; 19:142. [PMID: 30755156 PMCID: PMC6373072 DOI: 10.1186/s12879-019-3780-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 02/05/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Among different types of human papillomavirus (HPV), types 16 and 18 were known to be high-risk agents causing mainly cervical cancer. Up to now, the potential of HPV E7 protein has been proved as a diagnostic marker of cervical cancer. Moreover, the levels of anti-heat shock protein (Hsp) and anti-high mobility group box-1 (HMGB1) antibodies in cancer patients have been useful in tumor diagnosis. The goal of the present study was to determine the efficiency of the potential serologic markers including HPV E7, Hsp20, Hsp27 proteins and Hp91 peptide in Iranian HPV-exposed women, for the first time. METHODS At first, the recombinant HPV E7, Hsp20 and Hsp27 proteins were expressed in E. coli system, and purified by affinity chromatography under native conditions. Then, antibody responses were detected against the recombinant proteins as well as Hp91 peptide as potential markers in 49 Iranian women who were seropositive for HPV-16 and 18 L1 capsids (i.e., HPV-exposed women) and 49 controls using indirect ELISA. RESULTS Our data indicated that the seroreactivities of women exposed to HPV16, HPV18 and both of them against the recombinant E7, Hsp20, Hsp27 proteins and Hp91 peptide were significantly higher than those in control group (p < 0.05 for HPV16 or HPV18; p < 0.01 for both of them versus all markers). HPV-exposed women with high antibody responses to HPV-16 and 18 L1 capsids as a commercial biomarker had significant seroreactivity to HPV-16 and 18 E7 and Hsp27 (p < 0.05). The recombinant E7 and Hsp27 proteins showed higher efficiency than Hsp20 and Hp91 for detection of individuals exposed to HPV infections (p < 0.05). CONCLUSION Generally, the levels of serum E7 and Hsp27 were increased in HPV-16 and 18 L1- seropositive women suggesting their potential value as a diagnostic marker for HPV infections.
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Affiliation(s)
- Amitis Ramezani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Arezoo Aghakhani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Sepehr Soleymani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
| | - Anahita Bavand
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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Tobacco smoke and nicotine suppress expression of activating signaling molecules in human dendritic cells. Toxicol Lett 2018; 299:40-46. [PMID: 30227238 DOI: 10.1016/j.toxlet.2018.09.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 08/10/2018] [Accepted: 09/11/2018] [Indexed: 12/26/2022]
Abstract
Cigarette smoke has significant toxic effects on the immune system, and increases the risk of developing autoimmune diseases; one immunosuppressive effect of cigarette smoke is that it inhibits the T cell-stimulating, immunogenic properties of myeloid dendritic cells (DCs). As the functions of DCs are regulated by intra-cellular signaling pathways, we investigated the effects of cigarette smoke extract (CSE) and nicotine on multiple signaling molecules and other regulatory proteins in human DCs to elucidate the molecular basis of the inhibition of DC maturation and function by CSE and nicotine. Maturation of monocyte-derived DCs was induced with the TLR3-agonist poly I:C or with the TLR4-agonist lipopolysaccharide, in the absence or presence of CSE or nicotine. Reverse-phase protein microarray was used to quantify multiple signaling molecules and other proteins in cell lysates. Particularly in poly I:C-matured DCs, cigarette smoke constituents and nicotine suppressed the expression of signaling molecules associated with DC maturation and T cell stimulation, cell survival and cell migration. In conclusion, constituents of tobacco smoke suppress the immunogenic potential of DCs at the signaling pathway level.
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