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Yin Y, Zhang W, Zhao L, Li Y, Huang M, Han Y, Wu X. Development and validation of a predictive model for diagnosing EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis. BMC Cancer 2025; 25:397. [PMID: 40045277 PMCID: PMC11881351 DOI: 10.1186/s12885-025-13788-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/21/2025] [Indexed: 03/09/2025] Open
Abstract
PURPOSE This study aims to identify distinguishing factors between EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis and non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis. Additionally, we developed and validated a predictive diagnostic model based on these factors. METHODS To evaluate the early identification of individuals with EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis versus non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis, we carried out a retrospective cohort research. The medical records system included 148 individuals' diagnoses of EBV-associated hemophagocytic lymphohistiocytosis between 2015 and 2023. RESULTS In this study, 148 patients were included, 75 of whom had non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis and the remaining 73 had EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis. The highest AUC, with a good predictive value, was found for IL-10 > 39.87 pg/ml in separating EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis from non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis. The diagnosis of EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis was influenced by platelets < 33.5*109/L, IL-6 > 20.79 pg/ml, and IFN-γ > 12.12 pg/ml as independent variables. These factors were combined with the predictive value of IL-10 > 39.87 pg/ml to establish the predictive model of the nomogram for diagnosis. The training set's and validation set's areas under the ROC curves were 0.825 and 0.812, respectively, showing that the model had good discrimination, a well-calibrated model, and a clinically valid model as indicated by the clinical decision curve. CONCLUSION The results of this study showed that the prediction model based on platelets < 33.5*109/L, IL-6 > 20.79 pg/ml, IFN-γ > 12.12 pg/ml, and IL-10 > 39.87 pg/ml could more accurately distinguish between EBER-positive lymphoma-associated hemophagocytic lymphohistiocytosis and non-neoplastic EBV-associated hemophagocytic lymphohistiocytosis. This could aid clinicians in the early detection and convenient individualization of treatment for EBV-associated hemophagocytic lymphohistiocytosis.
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Affiliation(s)
- Yuhong Yin
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Wenzhi Zhang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Lizhen Zhao
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Ying Li
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Minchun Huang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Yu Han
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Xiaoyan Wu
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
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Yu H, Li J, Peng S, Liu Q, Chen D, He Z, Xiang J, Wang B. Tumor microenvironment: Nurturing cancer cells for immunoevasion and druggable vulnerabilities for cancer immunotherapy. Cancer Lett 2024; 611:217385. [PMID: 39645024 DOI: 10.1016/j.canlet.2024.217385] [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: 08/14/2024] [Revised: 09/29/2024] [Accepted: 12/04/2024] [Indexed: 12/09/2024]
Abstract
The tumor microenvironment (TME) is an intricate ecosystem where cancer cells thrive, encompassing a wide array of cellular and non-cellular components. The TME co-evolves with tumor progression in a spatially and temporally dynamic manner, which endows cancer cells with the adaptive capability of evading immune surveillance. To this end, diverse cancer-intrinsic mechanisms were exploited to dampen host immune system, such as upregulating immune checkpoints, impairing antigens presentation and competing for nutrients. In this review, we discuss how cancer immunoevasion is tightly regulated by hypoxia, one of the hallmark biochemical features of the TME. Moreover, we comprehensively summarize how immune evasiveness of cancer cells is facilitated by the extracellular matrix, as well as soluble components of TME, including inflammatory factors, lactate, nutrients and extracellular vesicles. Given their important roles in dictating cancer immunoevasion, various strategies to target TME components are proposed, which holds promising translational potential in developing novel therapeutics to sensitize anti-cancer immunotherapy such as immune checkpoint blockade.
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Affiliation(s)
- Hongyang Yu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Jinyang Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Shiyin Peng
- School of Medicine, Chongqing University, Chongqing, China
| | - Qin Liu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Dongfeng Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Zongsheng He
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China.
| | - Junyu Xiang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China.
| | - Bin Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China; Institute of Pathology and Southwest Cancer Center, And Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China; Jinfeng Laboratory, Chongqing, 401329, China.
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Zhang W, Wang M, Ji C, Liu X, Gu B, Dong T. Macrophage polarization in the tumor microenvironment: Emerging roles and therapeutic potentials. Biomed Pharmacother 2024; 177:116930. [PMID: 38878638 DOI: 10.1016/j.biopha.2024.116930] [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: 04/14/2024] [Revised: 05/31/2024] [Accepted: 06/09/2024] [Indexed: 07/28/2024] Open
Abstract
The tumor microenvironment (TME) is a combination of tumor cells and indigenous host stroma, which consists of tumor-infiltrating immune cells, endothelial cells, fibroblasts, pericytes, and non-cellular elements. Tumor-associated macrophages (TAMs) represent the major tumor-infiltrating immune cell type and are generally polarized into two functionally contradictory subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. Macrophage polarization refers to how macrophages are activated at a given time and space. The interplay between the TME and macrophage polarization can influence tumor initiation and progression, making TAM a potential target for cancer therapy. Here, we review the latest investigations on factors orchestrating macrophage polarization in the TME, how macrophage polarization affects tumor progression, and the perspectives in modulating macrophage polarization for cancer immunotherapy.
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Affiliation(s)
- Wenru Zhang
- Department of Natural Products Chemistry, Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
| | - Mengmeng Wang
- Department of Natural Products Chemistry, Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
| | - Chonghao Ji
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Xiaohui Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, China
| | - Bowen Gu
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States.
| | - Ting Dong
- Department of Natural Products Chemistry, Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
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Wang ZT, Deng ZM, Dai FF, Yuan MQ, Liu SY, Li BS, Cheng YX. Tumor immunity: A brief overview of tumor‑infiltrating immune cells and research advances into tumor‑infiltrating lymphocytes in gynecological malignancies (Review). Exp Ther Med 2024; 27:166. [PMID: 38476909 PMCID: PMC10928974 DOI: 10.3892/etm.2024.12453] [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: 07/26/2022] [Accepted: 01/03/2023] [Indexed: 03/14/2024] Open
Abstract
Tumor immunity is a promising topic in the area of cancer therapy. The 'soil' function of the tumor microenvironment (TME) for tumor growth has attracted wide attention from scientists. Tumor-infiltrating immune cells in the TME, especially the tumor-infiltrating lymphocytes (TILs), serve a key role in cancer. Firstly, relevant literature was searched in the PubMed and Web of Science databases with the following key words: 'Tumor microenvironment'; 'TME'; 'tumor-infiltrating immunity cells'; 'gynecologic malignancies'; 'the adoptive cell therapy (ACT) of TILs'; and 'TIL-ACT' (https://pubmed.ncbi.nlm.nih.gov/). According to the title and abstract of the articles, relevant items were screened out in the preliminary screening. The most relevant selected items were of two types: All kinds of tumor-infiltrating immune cells; and advanced research on TILs in gynecological malignancies. The results showed that the subsets of TILs were various and complex, while each subpopulation influenced each other and their effects on tumor prognosis were diverse. Moreover, the related research and clinical trials on TILs were mostly concentrated in melanoma and breast cancer, but relatively few focused on gynecological tumors. In conclusion, the present review summarized the biological classification of TILs and the mechanisms of their involvement in the regulation of the immune microenvironment, and subsequently analyzed the development of tumor immunotherapy for TILs. Collectively, the present review provides ideas for the current treatment dilemma of gynecological tumor immune checkpoints, such as adverse reactions, safety, personal specificity and efficacy.
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Affiliation(s)
- Zi-Tao Wang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhi-Min Deng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Fang-Fang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Meng-Qin Yuan
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Shi-Yi Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Bing-Shu Li
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yan-Xiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Liu Z, Xu X, Liu H, Zhao X, Yang C, Fu R. Immune checkpoint inhibitors for multiple myeloma immunotherapy. Exp Hematol Oncol 2023; 12:99. [PMID: 38017516 PMCID: PMC10685608 DOI: 10.1186/s40164-023-00456-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/02/2023] [Indexed: 11/30/2023] Open
Abstract
Multiple myeloma (MM) is related to immune disorders, recent studys have revealed that immunotherapy can greatly benefit MM patients. Immune checkpoints can negatively modulate the immune system and are closely associated with immune escape. Immune checkpoint-related therapy has attracted much attention and research in MM. However, the efficacy of those therapies need further improvements. There need more thoughts about the immune checkpoint to translate their use in clinical work. In our review, we aggregated the currently known immune checkpoints and their corresponding ligands, further more we propose various ways of potential translation applying treatment based on immune checkpoints for MM patients.
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Affiliation(s)
- Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xintong Xu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xianghong Zhao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Chun Yang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
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Yang J, Han F, Wu G, Dong Y, Su H, Xu J, Li J. Dysregulated B7H4/JAK2/STAT3 Pathway Involves in Hypertriglyceridemia Acute Pancreatitis and Is Attenuated by Baicalin. Dig Dis Sci 2023; 68:478-486. [PMID: 35781653 DOI: 10.1007/s10620-022-07606-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/21/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Patients with hypertriglyceridemia (HTG) are prone to develop more severe acute pancreatitis (AP). However, the specific molecular mechanism still has not been elaborated clearly, and effective drugs for treating HTG-AP are not yet readily available. Baicalin is an ingredient isolated from a natural product that with potential to attenuate inflammation and pain in AP. AIMS The aim of the present study was to explore the effect of baicalin on HTG-AP and the possible mechanism involved. METHODS A mouse model of HTG-AP was successfully established by administering Poloxamer 407 and L-arginine intraperitoneally. We analyzed pathological changes, and performed TUNEL staining, DHE staining, and western blot to detect apoptosis, inflammation, oxidative stress, and B7H4/JAK2/STAT3 signaling in the pancreas. RESULTS Treatment with baicalin decreased serum triglyceride, cholesterol, lipase, amylase levels, and attenuated pancreatic edema. After intervention with baicalin, apoptosis and inflammation in HTG-AP mice were alleviated, as indicated by the decrease of Bax, cleaved-caspase-3, IL-6, TNF-α, and IL-1β. Baicalin also alleviated oxidative stress by decreasing NOX2, increasing SOD2 protein expression, and regulating Nrf2/Keap1 signaling in HTG-AP mice. Furthermore, baicalin decreased the upregulated B7H4/JAK2/STAT3 pathway in HTG-AP. CONCLUSIONS In conclusion, our data suggested that baicalin could attenuate HTG-AP, possibly through regulating B7H4/JAK2/STAT3 signaling.
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Affiliation(s)
- Jie Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Fei Han
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Guanghai Wu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Ya Dong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Hang Su
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Jing Xu
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Jun Li
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
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Liu Z, Xu X, Zheng L, Ding K, Yang C, Huang J, Fu R. The value of serum IL-4 to predict the survival of MDS patients. Eur J Med Res 2023; 28:7. [PMID: 36600245 PMCID: PMC9811803 DOI: 10.1186/s40001-022-00948-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 12/13/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Immune indicators are routinely used for the detection of myelodysplastic syndrome (MDS), but these are not utilized as a reference indicator to assess prognosis in MDS-related prognostic evaluation systems, such as the World Health Organizational prognostic scoring system, the international prostate symptom score, and the revised international prostate symptom score. METHODS We examined immune indicators, including cluster of differentiation (CD)3, CD4, CD8, CD56, CD19, interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-a, and interferon-γ in 155 newly diagnosed MDS patients. We also conducted a correlation analysis with clinical indices. RESULTS IL-4 was found to be a predictor of survival in these 155 patients using the receiver operating characteristic curve, with 5.155 as the cut-off point. Patients with serum IL-4 levels ≥ 5.155 had a lower overall survival (OS) than those with IL-45.155 at diagnosis. Furthermore, multivariate analysis revealed that IL-4 levels > 5.155 were an independent predictor of OS (hazard ratio: 0.237; 95% confidence interval, 0.114-0.779; P = 0.013). In addition, serum IL-4 expression in the three different scoring systems showed significant differences in the survival of medium- to high-risk MDS patients (P = 0.014, P < 0.001, P < 0.001). CONCLUSIONS According to our study, IL-4 levels at the time of diagnosis can predict MDS prognosis in patients as a simple index reflecting host systemic immunity.
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Affiliation(s)
- Zhaoyun Liu
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
| | - Xintong Xu
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
| | - Likun Zheng
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
| | - Kai Ding
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
| | - Chun Yang
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
| | - Jincheng Huang
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
| | - Rong Fu
- grid.412645.00000 0004 1757 9434Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052 China
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Effect of B7-H4 downregulation induced by Toxoplasma gondii infection on dysfunction of decidual macrophages contributes to adverse pregnancy outcomes. Parasit Vectors 2022; 15:464. [PMID: 36514159 PMCID: PMC9746109 DOI: 10.1186/s13071-022-05560-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/20/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Toxoplasma gondii infection during pregnancy can lead to fetal defect(s) or congenital complications. The inhibitory molecule B7-H4 expressed on decidual macrophages (dMφ) plays an important role in maternal-fetal tolerance. However, the effect of B7-H4 on the function of dMφ during T. gondii infection remains unclear. METHODS Changes in B7-H4 expression on dMφ after T. gondii infection were explored both in vivo and in vitro. B7-H4-/- pregnant mice (pregnant mice with B7-H4 gene knockout) and purified primary human dMφ treated with B7-H4 neutralizing antibody were used to explore the role of B7-H4 signaling on regulating the membrane molecules, synthesis of arginine metabolic enzymes and cytokine production by dMφ with T. gondii infection. Also, adoptive transfer of dMφ from wild-type (WT) pregnant mice or B7-H4-/- pregnant mice to infected B7-H4-/- pregnant mice was used to examine the effect of B7-H4 on adverse pregnancy outcomes induced by T. gondii infection. RESULTS The results illustrated that B7-H4-/- pregnant mice infected by T. gondii had poorer pregnancy outcomes than their wild-type counterparts. The expression of B7-H4 on dMφ significantly decreased after T. gondii infection, which resulted in the polarization of dMφ from the M2 toward the M1 phenotype by changing the expression of membrane molecules (CD80, CD86, CD163, CD206), synthesis of arginine metabolic enzymes (Arg-1, iNOS) and production of cytokines (IL-10, TNF-α) production. Also, we found that the B7-H4 downregulation after T. gondii infection increased iNOS and TNF-α expression mediated through the JAK2/STAT1 signaling pathway. In addition, adoptive transfer of dMφ from a WT pregnant mouse donor rather than from a B7-H4-/- pregnant mouse donor was able to improve adverse pregnancy outcomes induced by T. gondii infection. CONCLUSIONS The results demonstrated that the downregulation of B7-H4 induced by T. gondii infection led to the dysfunction of decidual macrophages and contributed to abnormal pregnancy outcomes. Moreover, adoptive transfer of B7-H4+ dMφ could improve adverse pregnancy outcomes induced by T. gondii infection.
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Xiong X, Xie X, Wang Z, Zhang Y, Wang L. Tumor-associated macrophages in lymphoma: From mechanisms to therapy. Int Immunopharmacol 2022; 112:109235. [DOI: 10.1016/j.intimp.2022.109235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/24/2022] [Accepted: 09/03/2022] [Indexed: 11/05/2022]
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Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer. Immunity 2022; 55:701-717.e7. [PMID: 35364006 DOI: 10.1016/j.immuni.2022.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathway activated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 were expressed by the majority of human primary CRCs and metastases, which was associated with low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependent pathway controls anti-tumor immunity, revealing additional targets for immune checkpoint inhibition in microsatellite-stable CRC.
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Salkeni MA, Shin JY, Gulley JL. Resistance to Immunotherapy: Mechanisms and Means for Overcoming. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:45-80. [PMID: 34972962 DOI: 10.1007/978-3-030-79308-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Immune checkpoint blockade transformed cancer therapy during the last decade. However, durable responses remain uncommon, early and late relapses occur over the course of treatment, and many patients with PD-L1-expressing tumors do not respond to PD-(L)1 blockade. In addition, while some malignancies exhibit inherent resistance to treatment, others develop adaptations that allow them to evade antitumor immunity after a period of response. It is crucial to understand the pathophysiology of the tumor-immune system interplay and the mechanisms of immune escape in order to circumvent primary and acquired resistance. Here we provide an outline of the most well-defined mechanisms of resistance and shed light on ongoing efforts to reinvigorate immunoreactivity.
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Affiliation(s)
- Mohamad A Salkeni
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
| | - John Y Shin
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Alemohammad H, Najafzadeh B, Asadzadeh Z, Baghbanzadeh A, Ghorbaninezhad F, Najafzadeh A, Safarpour H, Bernardini R, Brunetti O, Sonnessa M, Fasano R, Silvestris N, Baradaran B. The importance of immune checkpoints in immune monitoring: A future paradigm shift in the treatment of cancer. Biomed Pharmacother 2021; 146:112516. [PMID: 34906767 DOI: 10.1016/j.biopha.2021.112516] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/20/2022] Open
Abstract
The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment.
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Affiliation(s)
- Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Arezoo Najafzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Safarpour
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, Catania, Italy
| | - Oronzo Brunetti
- Medical Oncological Unite, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Margherita Sonnessa
- Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Rossella Fasano
- Medical Oncological Unite, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy
| | - Nicola Silvestris
- Medical Oncological Unite, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Bari, Italy; Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, Bari, Italy.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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13
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Jiang Y, Ding Y, Liu S, Luo B. The role of Epstein–Barr virus-encoded latent membrane proteins in host immune escape. Future Virol 2021. [DOI: 10.2217/fvl-2020-0320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Epstein–Barr virus (EBV) is a type IV herpesvirus that widely infects the vast majority of adults, and establishes a latent infection pattern in host cells to escape the clearance of immune system. The virus is intimately associated with the occurrence and progression of lymphomas and epithelial cell cancers. EBV latent membrane proteins (LMPs) can assist its immune escape by downregulating host immune response. Besides EBV, LMPs have important effects on the functions of exosomes and autophagy, which also help EBV to escape immune surveillance. These escape mechanisms may provide conditions for further development of EBV-associated tumors. In this article, we discussed the potential functions of EBV-encoded LMPs in promoting immune escape.
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Affiliation(s)
- Yuanyuan Jiang
- Department of Medical Affairs of The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China
- Department of Pathogenic Biology, Qingdao University Medical College, 308 Ningxia Road, Qingdao, 266021, China
| | - Yuan Ding
- Department of Special Examination, Qingdao Women & Children Hospital, Qingdao, 266035, China
| | - Shuzhen Liu
- Department of Medical Affairs of The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Qingdao, 266000, China
| | - Bing Luo
- Department of Pathogenic Biology, Qingdao University Medical College, 308 Ningxia Road, Qingdao, 266021, China
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14
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Zhang W, Qiu Y, Xie X, Fu Y, Wang L, Cai Z. B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy? Front Oncol 2021; 11:647526. [PMID: 33869045 PMCID: PMC8044412 DOI: 10.3389/fonc.2021.647526] [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] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
T cells play a vital role in the immune responses against tumors. Costimulatory or coinhibitory molecules regulate T cell activation. Immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have shown remarkable benefits in patients with various tumor, but few patients have displayed significant immune responses against tumors after PD-1/PD-L1 immunotherapy and many have been completely unresponsive. Thus, researchers must explore novel immune checkpoints that trigger durable antitumor responses and improve clinical outcomes. In this regard, other B7 family checkpoint molecules have been identified, namely PD-L2, B7-H2, B7-H3, B7-H4 and B7-H6. The aim of the present article was to address the expression, clinical significance and roles of B7 family molecules in lymphoma, as well as in T and NK cell-mediated tumor immunity. B7 family checkpoints may offer novel and immunotherapeutic strategies for patients with lymphoma.
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Affiliation(s)
- Wei Zhang
- School of Clinical Medicine, Binzhou Medical University, Yantai, China.,Central Laboratory, Linyi People's Hospital, Linyi, China
| | - Yu Qiu
- School of Clinical Medicine, Binzhou Medical University, Yantai, China.,Central Laboratory, Linyi People's Hospital, Linyi, China
| | - Xiaoli Xie
- Central Laboratory, Linyi People's Hospital, Linyi, China
| | - Yao Fu
- Central Laboratory, Linyi People's Hospital, Linyi, China
| | - Lijuan Wang
- School of Clinical Medicine, Binzhou Medical University, Yantai, China.,Central Laboratory, Linyi People's Hospital, Linyi, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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15
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You L, Zhao Y, Kuca K, Wang X, Oleksak P, Chrienova Z, Nepovimova E, Jaćević V, Wu Q, Wu W. Hypoxia, oxidative stress, and immune evasion: a trinity of the trichothecenes T-2 toxin and deoxynivalenol (DON). Arch Toxicol 2021; 95:1899-1915. [PMID: 33765170 DOI: 10.1007/s00204-021-03030-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/15/2021] [Indexed: 01/05/2023]
Abstract
T-2 toxin and deoxynivalenol (DON) are type A and B trichothecenes, respectively. They widely occur as pollutants in food and crops and cause a series of toxicities, including immunotoxicity, hepatotoxicity, and neurotoxicity. Oxidative stress is the primary mechanistic basis of these toxic effects. Increasing amounts of evidence have shown that mitochondria are significant targets of apoptosis caused by T-2 toxin- and DON-induced oxidative stress via regulation of Bax/B-cell lymphoma-2 and caspase-3/caspase-9 signaling. DNA methylation and autophagy are involved in oxidative stress related to apoptosis, and hypoxia and immune evasion are related to oxidative stress in this context. Hypoxia induces oxidative stress by stimulating mitochondrial reactive oxygen species production and regulates the expression of cytokines, such as interleukin-1β and tumor necrosis factor-α. Programmed cell death-ligand 1 is upregulated by these cytokines and by hypoxia-inducible factor-1, which allows it to bind to programmed cell death-1 to enable escape of immune cell surveillance and achievement of immune evasion. This review concentrates on novel findings regarding the oxidative stress mechanisms of the trichothecenes T-2 toxin and DON. Importantly, we discuss the new evidence regarding the connection of hypoxia and immune evasion with oxidative stress in this context. Finally, the trinity of hypoxia, oxidative stress and immune evasion is highlighted. This work will be conducive to an improved understanding of the oxidative stress caused by trichothecene mycotoxins.
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Affiliation(s)
- Li You
- College of Life Science, Yangtze University, Jingzhou, 434025, China
| | - Yingying Zhao
- College of Life Science, Yangtze University, Jingzhou, 434025, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University (HZAU), Wuhan, China
| | - Patrik Oleksak
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic
| | - Zofia Chrienova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic
| | - Vesna Jaćević
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic
- Department for Experimental Toxicology and Pharmacology, National Poison Control Centre, Military Medical Academy, 11000, Belgrade, Serbia
- Department of Pharmacological Science, Medical Faculty of the Military Medical Academy, University of Defence, 11000, Belgrade, Serbia
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, 434025, China.
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic.
| | - Wenda Wu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, 500 03, Hradec Králové, Czech Republic.
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16
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Li X, Guo X, Ling J, Tang Z, Huang G, He L, Chen T. Nanomedicine-based cancer immunotherapies developed by reprogramming tumor-associated macrophages. NANOSCALE 2021; 13:4705-4727. [PMID: 33625411 DOI: 10.1039/d0nr08050k] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Tumor microenvironment is a complex ecosystem composed of tumor extracellular matrix, fibroblasts, blood vessels, and immune cells, promoting tumor development by secreting various growth factors, hydrolase, and inflammatory factors. Tumor-associated macrophages (TAMs) constitute the largest number of immune cells in the TME, and they have a "double-edged sword" effect on tumor growth, invasion, metastasis, angiogenesis, and immunosuppression. Under the regulation of different cytokines in the TME, the bidirectional TAMs can switch their phenotypes between tumoricidal M1-like and pro-tumorigenic M2-like macrophages. TAM polarization suggests that scientists can use this property to design drugs targeting this regulation as a promising immunotherapy strategy to enhance tumor therapy efficiency. In this review, we summarize a brief introduction of TAMs and their implications for tumorigenesis. Next, we review recent advances in designing various functionalized nanomedicines and their applications in nanomedicine-based cancer therapies that target TAMs by killing them, inhibiting macrophage recruitment, and repolarizing them from pro-tumorigenic M2-like to tumoricidal M1-like macrophages. Simultaneously, the regulation of nanomedicines on the signaling pathways accounting for these effects is also summarized. This review will not only provide background scientific information for the understanding of TAMs and their roles in cancer treatment but also help scientists design nanomedicines based on tumor TAMs, which can help achieve better clinical treatment outcomes for tumors.
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Affiliation(s)
- Xiaoying Li
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
| | - Xiaoming Guo
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
| | - Jiabao Ling
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
| | - Zheng Tang
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
| | - Guanning Huang
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
| | - Lizhen He
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
| | - Tianfeng Chen
- Department of Neurology and Stroke Center, The First Affiliated Hospital, and Department of Chemistry, Jinan University, Guangzhou 510632, China.
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17
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Gachpazan M, Akhlaghipour I, Rahimi HR, Saburi E, Mojarrad M, Abbaszadegan MR, Moghbeli M. Genetic and molecular biology of systemic lupus erythematosus among Iranian patients: an overview. AUTO- IMMUNITY HIGHLIGHTS 2021; 12:2. [PMID: 33516274 PMCID: PMC7847600 DOI: 10.1186/s13317-020-00144-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a clinicopathologically heterogeneous chronic autoimmune disorder affecting different organs and tissues. It has been reported that there is an increasing rate of SLE incidence among Iranian population. Moreover, the Iranian SLE patients have more severe clinical manifestations compared with other countries. Therefore, it is required to introduce novel methods for the early detection of SLE in this population. Various environmental and genetic factors are involved in SLE progression. MAIN BODY In present review we have summarized all of the reported genes which have been associated with clinicopathological features of SLE among Iranian patients. CONCLUSIONS Apart from the reported cytokines and chemokines, it was interestingly observed that the apoptosis related genes and non-coding RNAs were the most reported genetic abnormalities associated with SLE progression among Iranians. This review clarifies the genetics and molecular biology of SLE progression among Iranian cases. Moreover, this review paves the way of introducing an efficient panel of genetic markers for the early detection and better management of SLE in this population.
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Affiliation(s)
- Meisam Gachpazan
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarrad
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Huang YH, Cai K, Xu PP, Wang L, Huang CX, Fang Y, Cheng S, Sun XJ, Liu F, Huang JY, Ji MM, Zhao WL. CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis. Signal Transduct Target Ther 2021; 6:10. [PMID: 33431788 PMCID: PMC7801454 DOI: 10.1038/s41392-020-00437-8] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 11/13/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.
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Affiliation(s)
- Yao-Hui Huang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Cai
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.,School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Peng-Peng Xu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuan-Xin Huang
- Department of Immunobiology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Fang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shu Cheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Jian Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin-Yan Huang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng-Meng Ji
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Wei-Li Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
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19
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Desmirean M, Rauch S, Jurj A, Pasca S, Iluta S, Teodorescu P, Berce C, Zimta AA, Turcas C, Tigu AB, Moldovan C, Paris I, Steinheber J, Richlitzki C, Constantinescu C, Sigurjonsson OE, Dima D, Petrushev B, Tomuleasa C. B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974? J Clin Med 2020; 9:jcm9113412. [PMID: 33114418 PMCID: PMC7693982 DOI: 10.3390/jcm9113412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 10/15/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022] Open
Abstract
Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman.
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Affiliation(s)
- Minodora Desmirean
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
- Department of Pathology, Constantin Papilian Military Hospital, 400124 Cluj Napoca, Romania;
| | - Sebastian Rauch
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Ancuta Jurj
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Sergiu Pasca
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Sabina Iluta
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Patric Teodorescu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Cristian Berce
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (C.B.); (A.-A.Z.); (A.-B.T.); (C.M.); (B.P.)
| | - Alina-Andreea Zimta
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (C.B.); (A.-A.Z.); (A.-B.T.); (C.M.); (B.P.)
| | - Cristina Turcas
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Adrian-Bogdan Tigu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (C.B.); (A.-A.Z.); (A.-B.T.); (C.M.); (B.P.)
| | - Cristian Moldovan
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (C.B.); (A.-A.Z.); (A.-B.T.); (C.M.); (B.P.)
| | - Irene Paris
- Department of Pathology, Constantin Papilian Military Hospital, 400124 Cluj Napoca, Romania;
| | - Jakob Steinheber
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Cedric Richlitzki
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
| | - Catalin Constantinescu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
- Department of Anesthesia and Intensive Care, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania
| | - Olafur Eysteinn Sigurjonsson
- The Blood Bank, Landspitali—The National University Hospital of Iceland, 101 Reykjavik, Iceland;
- School of Science and Engineering, Reykjavik University, 101 Reykjavik, Iceland
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, 400124 Cluj Napoca, Romania;
| | - Bobe Petrushev
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (C.B.); (A.-A.Z.); (A.-B.T.); (C.M.); (B.P.)
- Department of Pathology, Octavian Fodor Regional Institute of Gastroenterology and Hepatology, 400124 Cluj Napoca, Romania
| | - Ciprian Tomuleasa
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj Napoca, Romania; (M.D.); (S.R.); (A.J.); (S.P.); (S.I.); (P.T.); (C.T.); (J.S.); (C.R.); (C.C.)
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, 400124 Cluj Napoca, Romania;
- Correspondence: ; Tel.: +40741337489
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20
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Nasrollahzadeh E, Razi S, Keshavarz-Fathi M, Mazzone M, Rezaei N. Pro-tumorigenic functions of macrophages at the primary, invasive and metastatic tumor site. Cancer Immunol Immunother 2020; 69:1673-1697. [PMID: 32500231 DOI: 10.1007/s00262-020-02616-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/16/2020] [Indexed: 12/19/2022]
Abstract
The tumor microenvironment (TME) not only facilitates cancer progression from the early formation to distant metastasis, but also it differs itself from time to time alongside the tumor evolution. Tumor-associated macrophages (TAMs), whether as pre-existing tissue-resident macrophages or recruited monocytes, are an inseparable part of this microenvironment. As their parents are broadly classified into a dichotomic, simplistic M1 and M2 subtypes, TAMs also exert paradoxical and diverse phenotypes as they are settled in different regions of TME and receive different microenvironmental signals. Briefly, M1 macrophages induce an inflammatory precancerous niche and flame the early oncogenic mutations, whereas their M2 counterparts are reprogrammed to release various growth factors and providing an immunosuppressive state in TME as long as abetting hypoxic cancer cells to set up a new vasculature. Further, they mediate stromal micro-invasion and co-migrate with invasive cancer cells to invade the vascular wall and neural sheath, while another subtype of TAMs prepares suitable niches much earlier than metastatic cells arrive at the target tissues. Accordingly, at the neoplastic transformation, during the benign-to-malignant transition and through the metastatic cascade, macrophages are involved in shaping the primary, micro-invasive and pre-metastatic TMEs. Whether their behavioral plasticity is derived from distinct genotypes or is fueled by microenvironmental cues, it could define these cells as remarkably interesting therapeutic targets.
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Affiliation(s)
- Elaheh Nasrollahzadeh
- School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, VIB, KU Leuven, Louvain, B3000, Belgium
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, 14194, Tehran, Iran. .,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. .,Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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21
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Wang JY, Wang WP. B7-H4, a promising target for immunotherapy. Cell Immunol 2019; 347:104008. [PMID: 31733822 DOI: 10.1016/j.cellimm.2019.104008] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 10/23/2019] [Accepted: 11/02/2019] [Indexed: 02/07/2023]
Abstract
The coinhibitory molecule B7-H4, an important member of the B7 family, is abnormally expressed in tumors, inflammation and autoimmune diseases. B7-H4 negatively regulates T cell immune response and promotes immune escape by inhibiting the proliferation, cytokine secretion, and cell cycle of T cells. Moreover, B7-H4 plays an extremely important role in tumorigenesis and tumor development including cell proliferation, invasion, metastasis, anti-apoptosis, etc. In addition, B7-H4 has the other biological functions, such as protection against type 1 diabetes (T1D) and islet cell transplantation. Therefore, B7-H4 has been identified as a novel marker or a therapeutic target for the treatment of tumors, inflammation, autoimmune diseases, and organ transplantation. Here, we summarized the expression profiles, physiological and pathological functions, and regulatory mechanisms of B7-H4, the signaling pathways involved, as well as B7-H4-based immunotherapy.
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Affiliation(s)
- Jia-Yu Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Wei-Peng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
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22
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Zhang J, Shi Z, Xu X, Yu Z, Mi J. The influence of microenvironment on tumor immunotherapy. FEBS J 2019; 286:4160-4175. [PMID: 31365790 PMCID: PMC6899673 DOI: 10.1111/febs.15028] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 06/24/2019] [Accepted: 07/29/2019] [Indexed: 12/13/2022]
Abstract
Tumor immunotherapy has achieved remarkable efficacy, with immune-checkpoint inhibitors as especially promising candidates for cancer therapy. However, some issues caused by immunotherapy have raised attention, such as limited efficacy for some patients, narrow antineoplastic spectrum, and adverse reactions, suggesting that using regulators of tumor immune response may prove to be more complicated than anticipated. Current evidence indicates that different factors collectively constituting the unique tumor microenvironment promote immune tolerance, and these include the expression of co-inhibitory molecules, the secretion of lactate, and competition for nutrients between tumor cells and immune cells. Furthermore, cancer-associated fibroblasts, the main cellular components of solid tumors, promote immunosuppression through inhibition of T cell function and extracellular matrix remodeling. Here, we summarize the research advances in tumor immunotherapy and the latest insights into the influence of microenvironment on tumor immunotherapy.
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Affiliation(s)
- Jieying Zhang
- Department of Biochemistry and Molecular Cell BiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineChina
- Research Center for Translational MedicineEast HospitalTongJi University School of MedicineShanghaiChina
| | - Zhaopeng Shi
- Department of Biochemistry and Molecular Cell BiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineChina
| | - Xiang Xu
- Department of Biochemistry and Molecular Cell BiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineChina
| | - Zuoren Yu
- Research Center for Translational MedicineEast HospitalTongJi University School of MedicineShanghaiChina
| | - Jun Mi
- Department of Biochemistry and Molecular Cell BiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineChina
- Hongqiao International Institute of MedicineTongren HospitalShanghai Jiao Tong University School of MedicineChina
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23
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Zhang J, Shi Z, Xu X, Yu Z, Mi J. The influence of microenvironment on tumor immunotherapy. THE FEBS JOURNAL 2019. [PMID: 31365790 DOI: 10.1111/febs.15028.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 09/29/2022]
Abstract
Tumor immunotherapy has achieved remarkable efficacy, with immune-checkpoint inhibitors as especially promising candidates for cancer therapy. However, some issues caused by immunotherapy have raised attention, such as limited efficacy for some patients, narrow antineoplastic spectrum, and adverse reactions, suggesting that using regulators of tumor immune response may prove to be more complicated than anticipated. Current evidence indicates that different factors collectively constituting the unique tumor microenvironment promote immune tolerance, and these include the expression of co-inhibitory molecules, the secretion of lactate, and competition for nutrients between tumor cells and immune cells. Furthermore, cancer-associated fibroblasts, the main cellular components of solid tumors, promote immunosuppression through inhibition of T cell function and extracellular matrix remodeling. Here, we summarize the research advances in tumor immunotherapy and the latest insights into the influence of microenvironment on tumor immunotherapy.
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Affiliation(s)
- Jieying Zhang
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China.,Research Center for Translational Medicine, East Hospital, TongJi University School of Medicine, Shanghai, China
| | - Zhaopeng Shi
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China
| | - Xiang Xu
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China
| | - Zuoren Yu
- Research Center for Translational Medicine, East Hospital, TongJi University School of Medicine, Shanghai, China
| | - Jun Mi
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China.,Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, China
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24
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Zeng Y, Li B, Liang Y, Reeves PM, Qu X, Ran C, Liu Q, Callahan MV, Sluder AE, Gelfand JA, Chen H, Poznansky MC. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment. FASEB J 2019; 33:6596-6608. [PMID: 30802149 PMCID: PMC6463916 DOI: 10.1096/fj.201802067rr] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 01/28/2019] [Indexed: 12/16/2022]
Abstract
Blockade of immune-checkpoint programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 can enhance effector T-cell responses. However, the lack of response in many patients to checkpoint-inhibitor therapies emphasizes the need for combination immunotherapies to pursue maximal antitumor efficacy. We have previously demonstrated that antagonism of C-X-C chemokine receptor type 4 (CXCR4) by plerixafor (AMD3100) can decrease regulatory T (Treg)-cell intratumoral infiltration. Therefore, a combination of these 2 therapies might increase antitumor effects. Here, we evaluated the antitumor efficacy of AMD3100 and anti-PD-1 (αPD-1) antibody alone or in combination in an immunocompetent syngeneic mouse model of ovarian cancer. We found that AMD3100, a highly specific CXCR4 antagonist, directly down-regulated the expression of both C-X-C motif chemokine 12 (CXCL12) and CXCR4 in vitro and in vivo in tumor cells. AMD3100 and αPD-1 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice when given as monotherapy. Combination of these 2 agents significantly enhanced antitumor effects compared with single-agent administration. Benefits of tumor control and animal survival were associated with immunomodulation mediated by these 2 agents, which were characterized by increased effector T-cell infiltration, increased effector T-cell function, and increased memory T cells in tumor microenvironment. Intratumoral Treg cells were decreased, and conversion of Treg cells into T helper cells was increased by AMD3100 treatment. Intratumoral myeloid-derived suppressor cells were decreased by the combined treatment, which was associated with decreased IL-10 and IL-6 in the ascites. Also, the combination therapy decreased suppressive leukocytes and facilitated M2-to-M1 macrophage polarization in the tumor. These results suggest that AMD3100 could be used to target the CXCR4-CXCL12 axis to inhibit tumor growth and prevent multifaceted immunosuppression alone or in combination with αPD-1 in ovarian cancer, which could be clinically relevant to patients with this disease.-Zeng, Y., Li, B., Liang, Y., Reeves, P. M., Qu, X., Ran, C., Liu, Q., Callahan, M. V., Sluder, A. E., Gelfand, J. A., Chen, H., Poznansky, M. C. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.
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Affiliation(s)
- Yang Zeng
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Binghao Li
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Yingying Liang
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Patrick M. Reeves
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Xiying Qu
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Chongzhao Ran
- Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and
| | - Qiuyan Liu
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China
| | - Michael V. Callahan
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Ann E. Sluder
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Jeffrey A. Gelfand
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Huabiao Chen
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Mark C. Poznansky
- Vaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
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25
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Jiang LN, Liu YB, Li BH. Lycopene exerts anti-inflammatory effect to inhibit prostate cancer progression. Asian J Androl 2019; 21:80-85. [PMID: 30198495 PMCID: PMC6337959 DOI: 10.4103/aja.aja_70_18] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 07/03/2018] [Indexed: 01/01/2023] Open
Abstract
Lycopene is a natural compound that alleviates oxidative stress and inflammation, exerting therapeutic effects in a number of cancers. The aim of this study is to investigate the efficacy of lycopene in inhibiting prostate cancer. Cell viability assays indicated the dose- and time-dependent toxicity of lycopene in prostate cancer cells. Annexin V/propidium iodide double-staining assays revealed the strong apoptotic effects of lycopene. The levels of inflammatory factors, including interleukin-1 (IL1), IL6, IL8, and tumor necrosis factor-α (TNF-α), in lycopene-treated cells were also reduced by lycopene treatment. With the increasing dose of lycopene, the survival of mice bearing prostate cancer xenografts was significantly improved ( P < 0.01), and the tumor burden was significantly reduced ( P < 0.01). Our results indicate that lycopene is a promising chemotherapy drug, which inhibits prostate cancer progression by suppressing the inflammatory response.
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Affiliation(s)
- Li-Ning Jiang
- Department of Surgery II, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
- Department of Urology Surgery I, Cangzhou Central Hospital, Cangzhou 061000, China
| | - Ya-Bin Liu
- Department of Surgery II, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Bing-Hui Li
- Department of Surgery II, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
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26
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Wang Y, Zhang X, Fan J, Chen W, Luan J, Nan Y, Wang S, Chen Q, Zhang Y, Wu Y, Ju D. Activating Autophagy Enhanced the Antitumor Effect of Antibody Drug Conjugates Rituximab-Monomethyl Auristatin E. Front Immunol 2018; 9:1799. [PMID: 30123222 PMCID: PMC6085421 DOI: 10.3389/fimmu.2018.01799] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/20/2018] [Indexed: 11/30/2022] Open
Abstract
Background Antibody drug conjugate (ADC) showed potent therapeutic efficacy in several types of cancers. The role of autophagy in antitumor effects of ADC remains unclear. Methods In this study, the ADC, Rituximab-monomethyl auristatin E (MMAE) with a Valine–Citrulline cleavable linker, was designed to investigate its therapeutic efficacy against non-Hodgkin lymphoma (NHL) as well as the underlying mechanisms. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) was used to detect growth inhibition in B-cell lymphoma cell lines, Ramos and Daudi cells, which were treated by Rituximab-MMAE alone or combined with autophagy conditioner. Apoptosis was detected by flow cytometry and immunohistochemistry, and apoptosis inhibitor was employed to discover the relationship between autophagy and apoptosis during the Rituximab-MMAE treatment. Autophagy was determined by three standard techniques which included confocal microscope, transmission electron microscope, and western blots. Ramos xenograft tumors in BALB/c nude mice were established to investigate the antitumor effect of combination use of Rituximab-MMAE and autophagy conditioner in B-NHL therapy. Results Our results showed that Rituximab-MMAE elicited caspase-3-dependent apoptosis in NHL cells and exhibited potent therapeutic efficacy in vivo. Autophagy, which was characterized by upregulated light chain 3-II expression, and accumulation of autophagosomes, was triggered during the Rituximab-MMAE treatment. Meanwhile, inactivation of Akt/mTOR pathway was shown to be involved in the autophagy triggered by Rituximab-MMAE, indicating a probable mechanism of the ADC-initiated autophagy. Importantly, inhibition of autophagy by chloroquine suppressed the Rituximab-MMAE-induced apoptosis, while activating autophagy by rapamycin significantly enhanced the therapeutic effect of Rituximab-MMAE both in vitro and in vivo. Conclusion Our data elucidated the critical relationship between autophagy and apoptosis in Rituximab-MMAE-based therapy and highlighted the potential approach for NHL therapy by combined administration of the ADC and autophagy activator.
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Affiliation(s)
- Yichen Wang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Xuyao Zhang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Jiajun Fan
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Wei Chen
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Jingyun Luan
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Yanyang Nan
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Shaofei Wang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Qicheng Chen
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Yujie Zhang
- Zhejiang Teruisi Pharmaceutical Co. Ltd., Huzhou, Zhejiang, China
| | - Youling Wu
- Zhejiang Teruisi Pharmaceutical Co. Ltd., Huzhou, Zhejiang, China
| | - Dianwen Ju
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
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Xie M, Li L, Zhu L, Zhou D, Yang X, Sun J, Zhu J, Zhu M, Zheng Y, Xie W, Ye X. An effective diagnostic index for lymphoma-associated hemophagocytic syndrome. QJM 2018; 111:541-547. [PMID: 29800321 DOI: 10.1093/qjmed/hcy103] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/22/2018] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Lymphoma-associated hemophagocytic syndrome (LAHS) is a highly fatal immune disorder. Poor prognosis is partly attributed to under diagnosis or delayed diagnosis. AIM Early identification of LAHS patients based on the laboratory findings could improve the outcomes. DESIGN Retrospective observational cross-sectional study. METHODS From January 2011 to June 2016, 282 adult patients with hemophagocytosis in bone marrow were enrolled, and 114 hemophagocytic lymphohistiocytosis (HLH) patients with definite underlying cause were finally included for analysis. The HLH patients were further divided into LAHS (76 out of 114) and non-malignancy-associated HLH (38 out of 114) groups. RESULTS Compared to non-malignancy-associated HLH, LAHS patients had significantly elevated lactate dehydrogenase (LDH) levels, increased thickness of spleen, higher proportion of patients with lymphadenopathy and significantly decreased peripheral blood cell count. In multivariate logistic regression model analysis, thickness of spleen ≥5 cm (OR = 17.9, 95%CI 1.35-236.6; P = 0.028), IL-6 level ≥55.1 pg/ml (OR = 12.01, 95%CI 1.03-138.9; P = 0.047) and IL-10 level ≥425.9 pg/ml (OR = 51.18, 95%CI 2.53-1035.1; P = 0.010) were independent predictors of LAHS diagnosis. Based on the regression parameters, we established a diagnostic index with weighted risk scores of 1 assigned to thickness of spleen and IL-6 level respectively, and a score of 3 assigned to IL-10 level. A diagnostic index ≥ 2 points had the best AUC value (0.889) with 84.2% of sensitivity and 93.7% of specificity for predicting LAHS. CONCLUSIONS LAHS can be considered when HLH patients have a diagnostic index ≥2 points, so actively looking for evidence of lymphoma and effective chemotherapy may be necessary.
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Affiliation(s)
- M Xie
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - L Li
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - L Zhu
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - D Zhou
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - X Yang
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - J Sun
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - J Zhu
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - M Zhu
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Y Zheng
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - W Xie
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - X Ye
- From the Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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Yang Q, Cao W, Wang Z, Zhang B, Liu J. Regulation of cancer immune escape: The roles of miRNAs in immune checkpoint proteins. Cancer Lett 2018; 431:73-84. [PMID: 29800685 DOI: 10.1016/j.canlet.2018.05.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/01/2018] [Accepted: 05/11/2018] [Indexed: 02/06/2023]
Abstract
Immune checkpoint proteins (ICPs) are regulators of immune system. The ICP dysregulation silences the host immune response to cancer-specific antigens, contributing to the occurrence and progress of various cancers. MiRNAs are regulatory molecules and function in mRNA silencing and post-transcriptional regulation of gene expression. MiRNAs that modulate the immunity via ICPs have received increasing attention. Many studies have shown that the expressions of ICPs are directly or indirectly repressed by miRNAs in multiple types of cancers. MiRNAs are also subject to regulation by ICPs. In this review, recent studies of the relationship between miRNAs and ICPs (including the PD-1, PD-L1, CTLA-4, ICOS, B7-1, B7-2, B7-H2, B7-H3, CD27, CD70, CD40, and CD40L) in cancer immune escape are comprehensively discussed, which provide critical detailed mechanistic insights into the functions of the miRNA-ICP axes and their effects on immune escape, and will be beneficial for the potential applications of immune checkpoint therapy and miRNA-based guidance for personalized medicine as well as for predicting the prognosis.
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Affiliation(s)
- Qin Yang
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China; School of Medical Laboratory, Shao Yang University, Hunan Province, 422000, China
| | - Wenjie Cao
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China; Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, 410013, China
| | - Zi Wang
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China; Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Bin Zhang
- Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, 410013, China.
| | - Jing Liu
- Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, China.
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B7-H6 expression is induced by lipopolysaccharide and facilitates cancer invasion and metastasis in human gliomas. Int Immunopharmacol 2018; 59:318-327. [PMID: 29679856 DOI: 10.1016/j.intimp.2018.03.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 03/19/2018] [Accepted: 03/20/2018] [Indexed: 01/09/2023]
Abstract
Although great progress has been made in treatment regimens, gliomas are still incurable and the 5-year survival remains poor. Studies focusing on molecules that regulate tumorigenesis or tumor immunity may provide potential therapeutic strategies for patients with glioma. B7-H6 is selectively expressed in tumor cells and plays vital roles in host immune responses. In this study, we demonstrated that B7-H6 was expressed in glioma cell lines, including CRT, U251, SHG-44, SF-295, TG-905 and U373, and tumor tissues isolated from glioma patients. Moreover, the expression levels of B7-H6 were significantly correlated with glioma grade. Previous studies reported that inflammatory mediators and cytokines induced the expression of B7 family members including programmed death-ligand 1, B7-H2 and B7-H4. Therefore, we explored the regulation of B7-H6 expression in gliomas and showed that lipopolysaccharide induced the expression of B7-H6 in glioma cells. To further analyze the roles of B7-H6 in gliomas, the expression of B7-H6 in glioma cells was knocked down. The results of cell counting kit-8, colony formation, wound healing, and transwell migration and invasion assays demonstrated that the proliferation, migration and invasion of glioma cells were inhibited after knocking down B7-H6. To elucidate the specific mechanisms of B7-H6 function in cancer progression, we examined the expression levels of proteins involved in cell apoptosis, migration and invasion. We demonstrated that the expression levels of E-cadherin and Bcl-2 associated X protein increased, and the expression levels of vimentin, N-cadherin, matrix metalloproteinase-2, matrix metalloproteinase-9 and survivin decreased after knocking down B7-H6. In conclusion, B7-H6 plays important roles in glioma, and targeting B7-H6 may provide a novel therapeutic strategy for glioma patients.
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30
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Liu YH, Ding Y, Gao CC, Li LS, Wang YX, Xu JD. Functional macrophages and gastrointestinal disorders. World J Gastroenterol 2018; 24:1181-1195. [PMID: 29568199 PMCID: PMC5859221 DOI: 10.3748/wjg.v24.i11.1181] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 02/12/2018] [Accepted: 02/25/2018] [Indexed: 02/06/2023] Open
Abstract
Macrophages (MΦ) differentiate from blood monocytes and participate in innate and adaptive immunity. Because of their abilities to recognize pathogens and activate bactericidal activities, MΦ are always discovered at the site of immune defense. MΦ in the intestine are unique, such that in the healthy intestine, they possess complex mechanisms to protect the gut from inflammation. In these complex mechanisms, they produce anti-inflammatory cytokines, such as interleukin-10 and transforming growth factor-β, and inhibit the inflammatory pathways mediated by Toll-like receptors. It has been demonstrated that resident MΦ play a crucial role in maintaining intestinal homeostasis, and they can be recognized by their unique markers. Nonetheless, in the inflamed intestine, the function of MΦ will change because of environmental variation, which may be one of the mechanisms of inflammatory bowel disease (IBD). We provide further explanation about these mechanisms in our review. In addition, we review recent discoveries that MΦ may be involved in the development of gastrointestinal tumors. We will highlight the possible therapeutic targets for the management of IBD and gastrointestinal tumors, and we also discuss why more details are needed to fully understand all other effects of intestinal MΦ.
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Affiliation(s)
- Yue-Hong Liu
- School of Basic Medical Science, Beijing Capital Medical University, Beijing 100069, China
| | - Yue Ding
- School of Basic Medical Science, Beijing Capital Medical University, Beijing 100069, China
| | - Chen-Chen Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- Function Platform Center, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Yue-Xiu Wang
- Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
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Tremble LF, Forde PF, Soden DM. Clinical evaluation of macrophages in cancer: role in treatment, modulation and challenges. Cancer Immunol Immunother 2017; 66:1509-1527. [PMID: 28948324 PMCID: PMC11028704 DOI: 10.1007/s00262-017-2065-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 09/13/2017] [Indexed: 12/22/2022]
Abstract
The focus of immunotherapeutics has been placed firmly on anti-tumour T cell responses. Significant progress has been made in the treatment of both local and systemic malignancies, but low response rates and rising toxicities are limiting this approach. Advancements in the understanding of tumour immunology are opening up a new range of therapeutic targets, including immunosuppressive factors in the tumour microenvironment. Macrophages are a heterogeneous group of cells that have roles in innate and adaptive immunity and tissue repair, but become co-opted by tumours to support tumour growth, survival, metastasis and immunosuppression. Macrophages also support tumour resistance to conventional therapy. In preclinical models, interference with macrophage migration, macrophage depletion and macrophage re-education have all been shown to reduce tumour growth and support anti-tumour immune responses. Here we discuss the role of macrophages in prognosis and sensitivity to therapy, while examining the significant progress which has been made in modulating the behaviour of these cells in cancer patients.
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Affiliation(s)
- Liam Friel Tremble
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Western Road, Cork, Ireland.
| | - Patrick F Forde
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Western Road, Cork, Ireland
| | - Declan M Soden
- Cork Cancer Research Centre, Western Gateway Building, University College Cork, Western Road, Cork, Ireland
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Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen-specific CD8 T cell exhaustion and suppressive innate immune cells. Oncotarget 2017; 8:82740-82753. [PMID: 29137299 PMCID: PMC5669925 DOI: 10.18632/oncotarget.21098] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 08/29/2017] [Indexed: 02/04/2023] Open
Abstract
B7x (B7-H4 or B7S1) is a coinhibitory member of the B7 immune checkpoint ligand family that regulates immune function following ligation with its unknown cognate receptors. B7x has limited expression on normal tissues, but is up-regulated on solid human tumors to inhibit anti-tumor immunity and associates with poor clinical prognosis. We assessed the contribution of cytokine stimuli to induce surface B7x expression on cancer cells and the role of tumor-expressed B7x in a murine pulmonary metastasis model, and finally evaluated the potential interaction between B7x and Neuropilin-1, a suggested potential cognate receptor. We showed that pro-inflammatory and anti-inflammatory cytokines IFNγ, TNFα, and IL-10 did not induce expression of B7x on human or murine cancer cells. Following i.v. injection of CT26, a murine colon cancer cell line in the BALB/c background, we observed a significant increase in tumor burden in the lung of B7x-expressing CT26 mice compared to B7x-negative parental CT26 control mice. This was marked by a significant increase in M2 tumor associated macrophages and antigen-specific CD8 T cell exhaustion. Finally, we found through multiple systems that there was no evidence for B7x and Neuropilin-1 direct interaction. Thus, the B7x pathway has an essential role in modulating the innate and adaptive immune cell infiltrate in the tumor microenvironment with its currently unknown cognate receptor(s).
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B7-H4 overexpression is essential for early hepatocellular carcinoma progression and recurrence. Oncotarget 2017; 8:80878-80888. [PMID: 29113351 PMCID: PMC5655246 DOI: 10.18632/oncotarget.20718] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 08/09/2017] [Indexed: 02/07/2023] Open
Abstract
B7-H4, another member of costimulatory molecule, has been shown to be overexpressed in multiple types of tumors, including hepatocellular carcinoma (HCC). However, the specific biological role of B7-H4 in HCC still needs to be further explored. In this study, we observed that B7-H4 was highly overexpressed in HCC tissues and cells, and its overexpression strongly correlated with patient's TNM stage, overall survival and early recurrence. Downregulation of B7-H4 significantly suppressed cell growth, invasion, and stemness of HCC by inducing apoptosis in the in vitro experiment. In addition, depletion of B7-H4 could help restore CD8+ T anti-tumor immunity by elevating the expression and secretion levels of CD107a, granzyme A, granzyme B, perforin and IFN-γ. In a xenografted mouse model of HCC, stable depletion of B7-H4 resulted in significantly smaller mean tumor volume and less mean tumor weight after 30 days of growth, compared to the control group. Together, our results provide insights into the diverse functions of B7-H4 involved in the pathogenesis, recurrence and anti-tumor immunity of HCC, indicating B7-H4 as a novel and effective approach for future treatment strategies that benefits anticancer therapy.
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Singh Y, Pawar VK, Meher JG, Raval K, Kumar A, Shrivastava R, Bhadauria S, Chourasia MK. Targeting tumor associated macrophages (TAMs) via nanocarriers. J Control Release 2017; 254:92-106. [DOI: 10.1016/j.jconrel.2017.03.395] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/29/2017] [Accepted: 03/30/2017] [Indexed: 12/13/2022]
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