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Seo YR, Kim HB, Jung H, Kim EG, Huh S, Yi EC, Kim KM. Unveiling transcriptional mechanisms of B7-H3 in breast cancer stem cells through proteomic approaches. iScience 2025; 28:112218. [PMID: 40230524 PMCID: PMC11995042 DOI: 10.1016/j.isci.2025.112218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/29/2024] [Accepted: 03/11/2025] [Indexed: 04/16/2025] Open
Abstract
B7-H3, an immune checkpoint molecule, is prominently overexpressed in various solid tumors, correlating with poor clinical outcomes. Despite its critical role in promoting tumorigenesis, metastasis, and immune evasion, the regulatory mechanisms governing B7-H3 expression, particularly in cancer stem cells (CSCs), remain elusive. In this comprehensive study, we focused on breast CSCs to uncover the transcriptional regulators driving B7-H3 overexpression. Utilizing DNA affinity purification-mass spectrometry (DAP-MS) to analyze B7-H3 promoter regions, we identified a novel set of transcription factors, including DDB1, XRCC5, PARP1, RPA1, and RPA3, as key modulators of B7-H3 expression. Functional assays revealed that targeting DDB1 with nitazoxanide significantly downregulated B7-H3 expression, subsequently impairing tumor sphere formation and cell migration in breast CSCs. These findings not only elucidate the complex transcriptional network controlling B7-H3 expression but also open new avenues for developing targeted immunotherapies aimed at disrupting CSC-driven cancer progression.
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Affiliation(s)
- Yu Ri Seo
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- Institute of Medical and Biological Engineering, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Han Byeol Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Hyeryeon Jung
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
| | - Eunhee G. Kim
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Sumin Huh
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Eugene C. Yi
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- Institute of Medical and Biological Engineering, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Kristine M. Kim
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, Republic of Korea
- Department of Systems Immunology, Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
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Mielcarska S, Kot A, Kula A, Dawidowicz M, Sobków P, Kłaczka D, Waniczek D, Świętochowska E. B7H3 in Gastrointestinal Tumors: Role in Immune Modulation and Cancer Progression: A Review of the Literature. Cells 2025; 14:530. [PMID: 40214484 PMCID: PMC11988818 DOI: 10.3390/cells14070530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
B7-H3 (CD276), a member of the B7 immune checkpoint family, plays a critical role in modulating immune responses and has emerged as a promising target in cancer therapy. It is highly expressed in various malignancies, where it promotes tumor evasion from T cell surveillance and contributes to cancer progression, metastasis, and therapeutic resistance, showing a correlation with the poor prognosis of patients. Although its receptors were not fully identified, B7-H3 signaling involves key intracellular pathways, including JAK/STAT, NF-κB, PI3K/Akt, and MAPK, driving processes crucial for supporting tumor growth such as cell proliferation, invasion, and apoptosis inhibition. Beyond immune modulation, B7-H3 influences cancer cell metabolism, angiogenesis, and epithelial-to-mesenchymal transition, further exacerbating tumor aggressiveness. The development of B7-H3-targeting therapies, including monoclonal antibodies, antibody-drug conjugates, and CAR-T cells, offers promising avenues for treatment. This review provides an up-to-date summary of the B7H3 mechanisms of action, putative receptors, and ongoing clinical trials evaluating therapies targeting B7H3, focusing on the molecule's role in gastrointestinal tumors.
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Affiliation(s)
- Sylwia Mielcarska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Anna Kot
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Agnieszka Kula
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Miriam Dawidowicz
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Piotr Sobków
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Daria Kłaczka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-514 Katowice, Poland; (A.K.); (M.D.); (D.W.)
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland; (A.K.); (P.S.); (D.K.)
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Du L, Zhang X, Huang L, Yang M, Zhang W, Xu J, Liu J, Xie W, Zhang X, Liu K, Zhai W, Wen L, Zhang B, Ye R, Liu L, Wang H, Sun H, Li D. Dual-Action flavonol carbonized polymer dots spray: Accelerating burn wound recovery through immune responses modulation and EMT induction. Mater Today Bio 2025; 31:101572. [PMID: 40034983 PMCID: PMC11872610 DOI: 10.1016/j.mtbio.2025.101572] [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: 11/22/2024] [Revised: 02/05/2025] [Accepted: 02/09/2025] [Indexed: 03/05/2025] Open
Abstract
Effective immune homeostasis modulation and re-epithelialization promotion are crucial for accelerating burn wound healing. Cell migration is fundamental to re-epithelialization, with epithelial-mesenchymal transition (EMT) as a key mechanism. A sustained inflammatory environment or impaired macrophage transition to M2 phenotype can hinder pro-resolving cytokine activation, further delaying the recruitment, migration, and re-epithelialization of epidermal cells to the injury site, ultimately compromising wound healing. Herein, the bioactive flavonol quercetin is transformed into pharmacologically active carbonized polymer dots (Qu-CDs) spray with high water dispersibility, permeability and biocompatibility for full-thickness skin burns treatment. Qu-CDs spray can efficiently initiate macrophage reprogramming and promote the transition of macrophages from M1 to M2 phenotype, modulating immune responses and facilitating the shift from the inflammatory phase to re-epithelialization. Additionally, Qu-CDs spray can promote cell migration and re-epithelialization of wound edge epithelial cells by inducing an EMT process without growth factors, further accelerating the reconstruction of the normal epidermal barrier. Mechanistically, Qu-CDs spray activates the smad1/5 signaling pathway for promoting the EMT phenotype of wound edge epithelial cells. Overall, this study facilitates the construction of novel spray dosage form of pharmacologically active carbonized polymer dots with desired bioactivities for effective wound healing.
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Affiliation(s)
- Liuyi Du
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Xu Zhang
- The Affiliated Stomatological Hospital of Soochow University, Suzhou Stomatological Hospital, Soochow University, Suzhou, 215000, PR China
| | - Lei Huang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Mingxi Yang
- Orthopedics Central Laboratory, Institute of Translational Medicine, The First Hospital of Jilin University, Jilin University, Changchun, 130021, PR China
| | - Wenbin Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Jiaqi Xu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Junguang Liu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Wangni Xie
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Xue Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Kexuan Liu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Wenhao Zhai
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Linlin Wen
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Boya Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Rongrong Ye
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Lijun Liu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Huan Wang
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China
| | - Hongchen Sun
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
| | - Daowei Li
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, PR China
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Zheng Y, Fuse H, Alzoubi I, Graeber MB. Microglia-Derived Brain Macrophages Associate with Glioblastoma Stem Cells: A Potential Mechanism for Tumor Progression Revealed by AI-Assisted Analysis. Cells 2025; 14:413. [PMID: 40136662 PMCID: PMC11940947 DOI: 10.3390/cells14060413] [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: 01/20/2025] [Revised: 02/21/2025] [Accepted: 03/08/2025] [Indexed: 03/27/2025] Open
Abstract
Background: Malignant gliomas, and notably glioblastoma, are highly aggressive brain tumors. Understanding the mechanisms underlying their progression is crucial for developing more effective treatments. Recent studies have highlighted the role of microglia and brain macrophages in glioblastoma development, but the specific interactions between these immune cells and glioblastoma stem cells (GSCs) remain unclear. Methods: To address this question, we have utilized AI-assisted cell recognition to investigate the spatial relationship between GSCs expressing high levels of CD276 (B7-H3) and microglia- and bone marrow-derived brain macrophages, respectively. Results: Using PathoFusion, our previously developed open-source AI framework, we were able to map specific immunohistochemical phenotypes at the single-cell level within whole-slide images. This approach enabled us to selectively identify Iba1+ and CD163+ macrophages as well as CD276+ GSCs with high specificity and to study their co-localization. Our analysis suggests a closer association of Iba1+ macrophages with GSCs than between CD163+ macrophages and GSCs in glioblastoma. Conclusions: Our findings provide novel insights into the spatial context of tumor immunity in glioblastoma and point to microglia-GSC interactions as a potential mechanism for tumor progression, especially during diffuse tissue infiltration. These findings have significant implications for our understanding of glioblastoma biology, providing a foundation for a comprehensive analysis of microglia activation phenotypes during glioma development. This, in turn, may lead to new therapeutic strategies targeting the early stages of the immune microenvironment of glioblastoma.
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Affiliation(s)
- Yuqi Zheng
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia;
| | - Haneya Fuse
- School of Medicine, Sydney Campus, University of Notre Dame, 160 Oxford Street, Darlinghurst, Sydney, NSW 2010, Australia;
| | - Islam Alzoubi
- School of Computer Science, The University of Sydney, J12/1 Cleveland St, Darlington, Sydney, NSW 2008, Australia;
| | - Manuel B. Graeber
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia;
- University of Sydney Association of Professors (USAP), University of Sydney, Sydney, NSW 2006, Australia
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Montoyo-Pujol YG, Ponce JJ, Delgado-García S, Martín TA, Ballester H, Castellón-Molla E, Ramos-Montoya A, Lozano-Cubo I, Sempere-Ortells JM, Peiró G. High CTLA-4 gene expression is an independent good prognosis factor in breast cancer patients, especially in the HER2-enriched subtype. Cancer Cell Int 2024; 24:371. [PMID: 39523362 PMCID: PMC11552348 DOI: 10.1186/s12935-024-03554-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-related death worldwide. This heterogeneous disease has been historically considered a non-immunogenic type of cancer. However, recent advances in immunotherapy have increased the interest in knowing the role of the immune checkpoints (IC) and other immune regulation pathways in this neoplasia. METHODS In this retrospective study, we evaluated the correlation of mRNA expression of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FOXO1 with clinicopathological factors and BC patient's outcome by real-time quantitative polymerase chain reaction (qPCR). RESULTS Our results showed that immunoregulatory gene expression depends on BC immunophenotype being CTLA-4 and PDCD1 (PD1) overexpressed on triple-negative/basal-like (TN/BL) and luminal B/HER2-positive phenotypes, respectively, and CD276 (B7-H3), JAK2 and FOXO1 associated with both luminal A and luminal B/HER2-negative tumors. In addition, we found that these genes can also be related to aggressive and non-aggressive clinicopathological characteristics in BC. Finally, survival analysis showed that CTLA-4 expression levels emerge as a significant independent factor of good prognosis in BC patients, especially in the HER2-enriched subtype. CONCLUSION Considering all these data, we can conclude that the expression of immunoregulatory genes depends on tumor phenotype and has potential clinical implications in BC patients.
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Affiliation(s)
- Yoel G Montoyo-Pujol
- Research Unit, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
- Medical Oncology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
| | - José J Ponce
- Medical Oncology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Silvia Delgado-García
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Tina A Martín
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Hortensia Ballester
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Elena Castellón-Molla
- Pathology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Angela Ramos-Montoya
- Gynecology and Obstetrics Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - Inmaculada Lozano-Cubo
- Medical Oncology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
| | - J Miguel Sempere-Ortells
- Research Unit, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n. 03080-San Vicente del Raspeig, Alicante, 03010, Spain
| | - Gloria Peiró
- Research Unit, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
- Pathology Department, Dr Balmis University General Hospital, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, Alicante, 03010, Spain.
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n. 03080-San Vicente del Raspeig, Alicante, 03010, Spain.
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Azizi M, Mokhtari Z, Tavana S, Bemani P, Heidari Z, Ghazavi R, Rezaei M. A Comprehensive Study on the Prognostic Value and Clinicopathological Significance of Different Immune Checkpoints in Patients With Colorectal Cancer: A Systematic Review and Meta-Analysis. CURRENT THERAPEUTIC RESEARCH 2024; 101:100760. [PMID: 39434898 PMCID: PMC11492099 DOI: 10.1016/j.curtheres.2024.100760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 08/30/2024] [Indexed: 10/23/2024]
Abstract
Background The prognostic significance of immune checkpoint expression in the tumor microenvironment has been widely investigated in colorectal cancers. However, the results of these studies are inconsistent and limited to some immune checkpoints. Objective The study aimed to investigate the correlation between different immune checkpoint expression and clinicopathological features and prognostic parameters. Methods We conducted a systematic review and meta-analysis of the published literature in PubMed, Web of Science-Core Collection, Scopus, Embase, and Cochrane databases to summarize the association between various immune checkpoints expression on both tumor cells and immune cells with clinicopathological features and prognostic parameters in patients with colorectal cancer. Results One hundred four studies incorporating 22,939 patients were included in our meta-analysis. Our results showed that among the B7 family, the high expression of B7H3, B7H4, PD-1, and PD-L1 on tumor cells and tumor tissue was significantly associated with higher T stage, advanced tumor, node, metastasis (TNM) stage, presence of vascular invasion, and lymphatic invasion. In addition, patients with high expression of B7H3, B7H4, PD-1, PD-L1, and PD-L2 were associated with shorter overall survival. High expression of PD-1 and PD-L1 in immune cells correlated with the absence of lymph node metastasis, lower TNM stage, early T stage, poor overall survival, and disease-free survival, respectively. Moreover, we found significant positive correlations between CD70 and Galectin-3 expression with advanced T stage. HLA-II overexpression was correlated with the absence of lymph node metastasis (odds ratio = 0.21, 95% CI = 0.11-0.38, P < 0.001) and early TNM stage (odds ratio = 0.35, 95% CI = 0.26-0.47, P < 0.001). Conclusions Overexpression of B7H3, B7H4, PD-1, PD-L1, PD-L2, CD70, and Galectin-3 on tumors is significantly associated with unfavorable clinicopathological characteristics and poor prognostic factors. Hence, these immune checkpoints can serve as predictive biomarkers for prognosis and the clinicopathological features of colorectal cancer because this is essential to identify patients suitable for anticancer therapy with immune checkpoint inhibitors.
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Affiliation(s)
- Mahdieh Azizi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Mokhtari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shirin Tavana
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Bemani
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Heidari
- Department of Biostatistics and Epidemiology, Faculty of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roghayeh Ghazavi
- Department of Knowledge and Information Science, Faculty of Education and Psychology, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Marzieh Rezaei
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Chavanton A, Mialhe F, Abrey J, Baeza Garcia A, Garrido C. LAG-3 : recent developments in combinational therapies in cancer. Cancer Sci 2024; 115:2494-2505. [PMID: 38702996 PMCID: PMC11309939 DOI: 10.1111/cas.16205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/11/2024] [Accepted: 04/17/2024] [Indexed: 05/06/2024] Open
Abstract
The study of anticancer immune responses and in particular the action of immune checkpoint inhibitors that overcome T cell inhibition has revolutionized metastatic patients' care. Unfortunately, many patients are resistant to these innovative immunotherapies. Over the last decade, several immune checkpoint inhibitors, currently available in the clinic, have been developed, such as anti-PD-1/PD-L1 or anti-CTLA-4. More recently, other immune checkpoints have been characterized, among them lymphocyte activation gene 3 (LAG-3). LAG-3 has been the subject of numerous therapeutic studies and may be involved in cancer-associated immune resistance phenomena. This review summarizes the latest knowledge on LAG-3 as an immunotherapeutic target, particularly in combination with standard or innovative therapies. Indeed, many studies are looking at combining LAG-3 inhibitors with chemotherapeutic, immunotherapeutic, radiotherapeutic treatments, or adoptive cell therapies to potentiate their antitumor effects and/or to overcome patients' resistance. We will particularly focus on the association therapies that are currently in phase III clinical trials and innovative combinations in preclinical phase. These new discoveries highlight the possibility of developing other types of therapeutic combinations currently unavailable in the clinic, which could broaden the therapeutic spectrum of personalized medicine.
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Affiliation(s)
- Aude Chavanton
- INSERM, UMR 1231Laboratoire d'Excellence LipSTIC and « Equipe labellisée par la Ligue Nationale contre le Cancer »DijonFrance
- Faculty of MedicineUniversité de BourgogneDijonFrance
| | - Flavie Mialhe
- INSERM, UMR 1231Laboratoire d'Excellence LipSTIC and « Equipe labellisée par la Ligue Nationale contre le Cancer »DijonFrance
- Faculty of MedicineUniversité de BourgogneDijonFrance
| | - Jimena Abrey
- INSERM, UMR 1231Laboratoire d'Excellence LipSTIC and « Equipe labellisée par la Ligue Nationale contre le Cancer »DijonFrance
- Faculty of MedicineUniversité de BourgogneDijonFrance
| | - Alvaro Baeza Garcia
- INSERM, UMR 1231Laboratoire d'Excellence LipSTIC and « Equipe labellisée par la Ligue Nationale contre le Cancer »DijonFrance
- Faculty of MedicineUniversité de BourgogneDijonFrance
| | - Carmen Garrido
- INSERM, UMR 1231Laboratoire d'Excellence LipSTIC and « Equipe labellisée par la Ligue Nationale contre le Cancer »DijonFrance
- Faculty of MedicineUniversité de BourgogneDijonFrance
- Center for Cancer Georges‐François LeclercDijonFrance
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Zhang ZY, Xu JH, Zhang JL, Lin YX, Ou-Yang J. Pro-cancer role of CD276 as a novel biomarker for clear cell renal cell carcinoma. Urol Oncol 2024; 42:247.e1-247.e10. [PMID: 38600002 DOI: 10.1016/j.urolonc.2024.03.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/21/2024] [Accepted: 03/28/2024] [Indexed: 04/12/2024]
Abstract
OBJECTIVE Renal cell carcinoma (RCC) is a common malignant tumor with a high incidence in males and the elderly, and clear cell RCC (ccRCC) is the most common RCC subtype. ccRCC is highly metastatic with a poor prognosis. Therefore, it is crucial to obtain a detailed understanding of the molecular mechanism of ccRCC and to identify suitable biomarkers to realize early diagnosis and improve prognosis. METHODS We analyzed data from the Cancer Genome Atlas, investigated the overall differential expression of CD276 in ccRCC, and evaluated the influence of CD276 on patient survival and prognosis. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis and investigated cell infiltration and drug responsiveness to further assess the regulatory effect of CD276 on ccRCC. Furthermore, we verified CD276 expression in RCC cell lines and control cell lines. RESULTS The CD276 expression level in ccRCC samples was higher than that in corresponding samples adjacent to the tumors. Moreover, high CD276 expression levels were positively correlated with poor prognosis in patients with RCC. GSEA revealed that CD276 was significantly involved in immune-related pathways, and the level of CD276 expression was confirmed as associated with immune cell infiltration to some extent. Notably, some drugs were predicted to act on CD276, and this was confirmed by molecular docking. Furthermore, high levels of CD276 expression in RCC cell lines were verified. CONCLUSION CD276 expression was significantly increased in ccRCC tissues and cells and positively correlated with patient prognosis. CD276 is a potential prognostic biomarker of ccRCC. Overall, this study provides a potential therapeutic strategy for ccRCC.
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Affiliation(s)
- Zhi-Yu Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Jian-Hao Xu
- Department of Pathology, The First People's Hospital of Kunshan, Suzhou 215300, Jiangsu, China
| | - Jiang-Lei Zhang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Yu-Xin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
| | - Jun Ou-Yang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China.
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Liu WF, Jiang QY, Qi ZR, Zhang F, Tang WQ, Wang HQ, Dong L. CD276 Promotes an Inhibitory Tumor Microenvironment in Hepatocellular Carcinoma and is Associated with Poor Prognosis. J Hepatocell Carcinoma 2024; 11:1357-1373. [PMID: 39011124 PMCID: PMC11247130 DOI: 10.2147/jhc.s469529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/19/2024] [Indexed: 07/17/2024] Open
Abstract
Background CD276 is an emerging immune checkpoint molecule that has been implicated in various cancers. However, its specific role in hepatocellular carcinoma (HCC) remains unclear. This study examined the impact of CD276 on patient prognosis and the tumor microenvironment (TME). Methods The Cancer Genome Atlas (TCGA) database was utilized to evaluate CD276 expression in HCC and the association between CD276 and immune indicators was also analyzed. The signaling pathways correlated with CD276 expression were identified by gene set enrichment analysis (GSEA). Different algorithms were used to assess immune cell infiltration. The effect of CD276 knockdown on HCC cell phenotypes and its relationship with macrophage polarization was examined using the cell counting kit 8 (CCK-8) assay and co-culture system. Results CD276 was upregulated in HCC and associated with unfavorable clinical outcomes. Hgh CD276 expression was associated with enrichment of the G2/M checkpoint, E2F targets, and mitotic spindles. CD276 expression was correlated with the infiltration of immune cells, including high level of tumor-associated macrophages and low levels of CD8+ T cells. Knockdown of CD276 decreased HCC cell proliferation and increased apoptosis. CD276 silencing in HCC cells and co-culture with THP-1-derived macrophages had a regulatory effect on macrophage polarization and macrophage-mediated cell proliferation and migration. Conclusion CD276 expression in HCC is associated with unfavorable clinical outcomes and may contribute to the development of an immunosuppressive microenvironment. Specifically, CD276 was associated with alterations in immune cell infiltration, immune marker expression, and macrophage polarization during HCC progression, suggesting its potential as a prognostic indicator and promising target for immunotherapeutic intervention in HCC.
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Affiliation(s)
- Wen-Feng Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qiu-Yu Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhuo-Ran Qi
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Feng Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Wen-Qing Tang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Hao-Qi Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
- Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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Hu C, Wang S, Wang J, Ruan X, Wu L, Zhang Z, Wang X, Zhang J, Liu Y, Li Y, Zhao X. B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α. J Gastrointest Oncol 2024; 15:1035-1049. [PMID: 38989423 PMCID: PMC11231846 DOI: 10.21037/jgo-24-384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 06/21/2024] [Indexed: 07/12/2024] Open
Abstract
Background B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.
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Affiliation(s)
- Chenrui Hu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of General Surgery, The Fifth People's Hospital of Jinan, Jinan, China
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shengjia Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jin Wang
- Department of General Surgery, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, China
| | - Xiaokang Ruan
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Linwei Wu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhe Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, China
| | - Xuefeng Wang
- Department of Biochemistry and Molecular Biology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China
| | - Jianglei Zhang
- Department of Urology Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yonghao Liu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yao Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Zhao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
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11
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Zhang X, Xu C, Wang C, Pei Y, He M, Wan Z, Hou J, Wang L. CD276 promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma through the TGF-β/SMAD signaling. Clin Exp Metastasis 2024; 41:81-90. [PMID: 38396262 DOI: 10.1007/s10585-024-10280-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 02/06/2024] [Indexed: 02/25/2024]
Abstract
OBJECTIVE Aberrant expression of CD276 has been reported in malignant tumors. However, the exact role and mechanisms of CD276 influence the progression of esophageal squamous cell carcinoma (ESCC) still need to be understood. METHODS Bioinformatics analysis of data from The Cancer Genome Atlas and Gene Expression Omnibus databases, along with immunohistochemistry staining, was used to explore the expression patterns of CD276 in ESCC. Cell counting kit-8 and Transwell assays were employed to evaluate the effects of CD276 expression on tumor cell proliferation and motility. Western blotting and Transwell assays were used to explore the potential pathways through which CD276 mediates the progression of ESCC. Moreover, the in vivo role of CD276 in tumor progression was investigated by establishing a lung metastasis mouse model. RESULTS A significant upregulation of CD276 was observed in ESCC tissues compared to adjacent tissues. The inhibition of CD276 had no evident impact on ESCC cell proliferation but notably hindered their migratory and invasive properties and the expression of epithelial-mesenchymal transition (EMT) markers. Inversely, overexpressing CD276 led to an upregulation of EMT markers, underscoring the capacity of CD276 to amplify the motility of ESCC cells. Furthermore, CD276 was found to enhance the migratory and invasive abilities of ESCC cells by activating the TGF-β/SMAD signaling but not the PI3K/AKT pathway. In vivo studies demonstrated that CD276 facilitates pulmonary metastasis. CONCLUSION CD276 is significant upregulation in ESCC tissues and facilitates the EMT process in ESCC cells via the TGF-β/SMAD signaling, thus promoting the progression of ESCC.
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Affiliation(s)
- Xiaoman Zhang
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Cuicui Xu
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Cuicui Wang
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yuhui Pei
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Min He
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Zhicheng Wan
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Jun Hou
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
| | - Lianghai Wang
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
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12
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Varghese E, Samuel SM, Brockmueller A, Shakibaei M, Kubatka P, Büsselberg D. B7-H3 at the crossroads between tumor plasticity and colorectal cancer progression: a potential target for therapeutic intervention. Cancer Metastasis Rev 2024; 43:115-133. [PMID: 37768439 PMCID: PMC11016009 DOI: 10.1007/s10555-023-10137-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023]
Abstract
B7-H3 (B7 homology 3 protein) is an important transmembrane immunoregulatory protein expressed in immune cells, antigen-presenting cells, and tumor cells. Studies reveal a multifaceted role of B7-H3 in tumor progression by modulating various cancer hallmarks involving angiogenesis, immune evasion, and tumor microenvironment, and it is also a promising candidate for cancer immunotherapy. In colorectal cancer (CRC), B7-H3 has been associated with various aspects of disease progression, such as evasion of tumor immune surveillance, tumor-node metastasis, and poor prognosis. Strategies to block or interfere with B7-H3 in its immunological and non-immunological functions are under investigation. In this study, we explore the role of B7-H3 in tumor plasticity, emphasizing tumor glucose metabolism, angiogenesis, epithelial-mesenchymal transition, cancer stem cells, apoptosis, and changing immune signatures in the tumor immune landscape. We discuss how B7-H3-induced tumor plasticity contributes to immune evasion, metastasis, and therapy resistance. Furthermore, we delve into the most recent advancements in targeting B7-H3-based tumor immunotherapy as a potential approach to CRC treatment.
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Affiliation(s)
- Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, 80336, Munich, Germany
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, 80336, Munich, Germany
| | - Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 036 01, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar.
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13
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Chen R, Su F, Zhang T, Wu D, Yang J, Guan Q, Chai C. N6-methyladenosine modification of B7-H3 mRNA promotes the development and progression of colorectal cancer. iScience 2024; 27:108956. [PMID: 38318386 PMCID: PMC10839442 DOI: 10.1016/j.isci.2024.108956] [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: 07/26/2023] [Revised: 12/29/2023] [Accepted: 01/15/2024] [Indexed: 02/07/2024] Open
Abstract
B7-H3 is a common oncogene found in various cancer types. However, the molecular mechanisms underlying abnormal B7-H3 expression and colorectal cancer (CRC) progression need to be extensively explored. B7-H3 was upregulated in human CRC tissues and its abnormal expression was correlated with a poor prognosis in CRC patients. Notably, gain- and loss-of-function experiments revealed that B7-H3 knockdown substantially inhibited cell proliferation, migration, and invasion in vitro, whereas exogenous B7-H3 expression yielded contrasting results. In addition, silencing of B7-H3 inhibited tumor growth in a xenograft mouse model. Mechanistically, our study demonstrated that the N6-methyladenosine (m6A) binding protein YTHDF1 augmented B7-H3 expression in an m6A-dependent manner. Furthermore, rescue experiments demonstrated that reintroduction of B7-H3 considerably abolished the inhibitory effects on cell proliferation and invasion induced by silencing YTHDF1. Our results suggest that the YTHDF1-m6A-B7-H3 axis is crucial for CRC development and progression and may represent a potential therapeutic target for CRC treatment.
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Affiliation(s)
- Rui Chen
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Fei Su
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Tao Zhang
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Dongjin Wu
- People’s Hospital of Suzhou New District, Suzhou, Jiangsu 215000, P.R. China
| | - Jingru Yang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Quanlin Guan
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Oncology Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Chen Chai
- People’s Hospital of Suzhou New District, Suzhou, Jiangsu 215000, P.R. China
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14
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Alzoubi I, Zhang L, Zheng Y, Loh C, Wang X, Graeber MB. PathoGraph: An Attention-Based Graph Neural Network Capable of Prognostication Based on CD276 Labelling of Malignant Glioma Cells. Cancers (Basel) 2024; 16:750. [PMID: 38398141 PMCID: PMC10886785 DOI: 10.3390/cancers16040750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Computerized methods have been developed that allow quantitative morphological analyses of whole slide images (WSIs), e.g., of immunohistochemical stains. The latter are attractive because they can provide high-resolution data on the distribution of proteins in tissue. However, many immunohistochemical results are complex because the protein of interest occurs in multiple locations (in different cells and also extracellularly). We have recently established an artificial intelligence framework, PathoFusion which utilises a bifocal convolutional neural network (BCNN) model for detecting and counting arbitrarily definable morphological structures. We have now complemented this model by adding an attention-based graph neural network (abGCN) for the advanced analysis and automated interpretation of such data. Classical convolutional neural network (CNN) models suffer from limitations when handling global information. In contrast, our abGCN is capable of creating a graph representation of cellular detail from entire WSIs. This abGCN method combines attention learning with visualisation techniques that pinpoint the location of informative cells and highlight cell-cell interactions. We have analysed cellular labelling for CD276, a protein of great interest in cancer immunology and a potential marker of malignant glioma cells/putative glioma stem cells (GSCs). We are especially interested in the relationship between CD276 expression and prognosis. The graphs permit predicting individual patient survival on the basis of GSC community features. Our experiments lay a foundation for the use of the BCNN-abGCN tool chain in automated diagnostic prognostication using immunohistochemically labelled histological slides, but the method is essentially generic and potentially a widely usable tool in medical research and AI based healthcare applications.
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Affiliation(s)
- Islam Alzoubi
- School of Computer Science, The University of Sydney, J12/1 Cleveland St, Darlington, Sydney, NSW 2008, Australia; (I.A.); (L.Z.)
| | - Lin Zhang
- School of Computer Science, The University of Sydney, J12/1 Cleveland St, Darlington, Sydney, NSW 2008, Australia; (I.A.); (L.Z.)
| | - Yuqi Zheng
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia; (Y.Z.); (C.L.)
| | - Christina Loh
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia; (Y.Z.); (C.L.)
| | - Xiuying Wang
- School of Computer Science, The University of Sydney, J12/1 Cleveland St, Darlington, Sydney, NSW 2008, Australia; (I.A.); (L.Z.)
| | - Manuel B. Graeber
- Ken Parker Brain Tumour Research Laboratories, Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia; (Y.Z.); (C.L.)
- University of Sydney Association of Professors (USAP), University of Sydney, Sydney, NSW 2006, Australia
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15
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Chen LC, Yang PC, Chen CY, Chiang SF, Chen TW, Chen WTL, Ke TW, Liang JA, Shiau A, Chao KSC, Huang KCY. Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma. J Cancer 2024; 15:1750-1761. [PMID: 38370387 PMCID: PMC10869969 DOI: 10.7150/jca.91089] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/18/2024] [Indexed: 02/20/2024] Open
Abstract
Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells in vitro and in vivo. Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.
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Affiliation(s)
- Liang-Chi Chen
- Department of Pathology, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Pei-Chen Yang
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Chia-Yi Chen
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Shu-Fen Chiang
- Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 42055, Taiwan
| | - Tsung-Wei Chen
- Department of Pathology, Asia University Hospital, Asia University, Taichung 41354, Taiwan
| | - William Tzu-Liang Chen
- Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu 302, Taiwan
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Surgery, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Tao-Wei Ke
- Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - Ji-An Liang
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - An‑Cheng Shiau
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan
| | - K. S. Clifford Chao
- Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Radiotherapy, School of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Kevin Chih-Yang Huang
- Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan
- Translation Research Core, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 40402, Taiwan
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16
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Zhang H, Zhu M, Zhao A, Shi T, Xi Q. B7-H3 regulates anti-tumor immunity and promotes tumor development in colorectal cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189031. [PMID: 38036107 DOI: 10.1016/j.bbcan.2023.189031] [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: 09/19/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract and one of the most common causes of cancer-related deaths worldwide. Immune checkpoint inhibitors have become a milestone in many cancer treatments with significant curative effects. However, its therapeutic effect on colorectal cancer is still limited. B7-H3 is a novel immune checkpoint molecule of the B7/CD28 family and is overexpressed in a variety of solid tumors including colorectal cancer. B7-H3 was considered as a costimulatory molecule that promotes anti-tumor immunity. However, more and more studies support that B7-H3 is a co-inhibitory molecule and plays an important immunosuppressive role in colorectal cancer. Meanwhile, B7-H3 promoted metabolic reprogramming, invasion and metastasis, and chemoresistance in colorectal cancer. Therapies targeting B7-H3, including monoclonal antibodies, antibody drug conjugations, and chimeric antigen receptor T cells, have great potential to improve the prognosis of colorectal cancer patients.
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Affiliation(s)
- Huan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Mengxin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Anjing Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Qinhua Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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Imodoye SO, Adedokun KA. EMT-induced immune evasion: connecting the dots from mechanisms to therapy. Clin Exp Med 2023; 23:4265-4287. [PMID: 37966552 DOI: 10.1007/s10238-023-01229-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/18/2023] [Indexed: 11/16/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a dynamic program crucial for organismal development and tissue regeneration. Unfortunately, this program is often hijacked by epithelial tumors to facilitate metastasis. Beyond its role in cancer spread, EMT increases cancer cell survival by activating stem cell programs and bypassing apoptotic programs. Importantly, the capacity of EMT to enforce tumor progression by altering the tumor cell phenotype without triggering immune responses opens the intriguing possibility of a mechanistic link between EMT-driven cancers and immune evasion. Indeed, EMT has been acknowledged as a of driver immune evasion, but the mechanisms are still evolving. Here, we review recent insights into the influence of EMT on tumor immune evasion. Specifically, we focus on the mechanistic roles of EMT in immune escape as the basis that may provide a platform for innovative therapeutic approaches in advanced tumors. We summarize promising therapeutic approaches currently in clinical trials and trending preclinical studies aimed at reinvigorating the tumor microenvironment to create immune-permissive conditions that facilitates immune-mediated tumor clearance. We anticipate that this will assist researchers and pharmaceutical companies in understanding how EMT compromises the immune response, potentially paving the way for effective cancer therapies.
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Affiliation(s)
- Sikiru O Imodoye
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.
| | - Kamoru A Adedokun
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
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18
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Chen W, Hu J, He Y, Yu L, Liu Y, Cheng Y, Jia B, Li X, Yu G, Wang Y. The Interaction Between SMAD1 and YAP1 Is Correlated with Increased Resistance of Gastric Cancer Cells to Cisplatin. Appl Biochem Biotechnol 2023; 195:6050-6067. [PMID: 36418715 DOI: 10.1007/s12010-022-04253-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2022] [Indexed: 11/25/2022]
Abstract
Drug resistance is a major obstacle leading to treating failure and poor outcome in gastric cancer (GC). This study explores the interaction between SMAD family member 1 (SMAD1) and Yes1-associated transcriptional regulator (YAP1) and their roles in cisplatin (DDP) resistance in GC. Transcriptome analysis predicted that SMAD1 is highly expressed in DDP-resistant cells. Elevated SMAD1 expression was detected in GC tissue and cells, especially in DDP-resistant cells (MKN-45/DDP and AGS/DDP). SMAD1 downregulation in cells decreased 50% inhibition value of DDP, reduced proliferation, migration, and invasion, and promoted cell cycle arrest and apoptosis. A protein-protein interaction network suggested a possible SMAD1 and YAP1 interaction in GC. The SMAD1 and YAP1 interaction was validated by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and luciferase assays. SMAD1 bound to YAP1 and activated its transcription. SMAD1 formed complexes with YAP1 in nucleus, and YAP1 upregulation enhanced SMAD1 activity as well. Upregulation of YAP1 restored the malignant behaviors of GC cells suppressed by SMAD1 silencing. In vivo, SMAD1 silencing suppressed growth and DDP resistance of xenograft tumors in nude mice, and this suppression was blocked by YAP1 overexpression again. In conclusion, this study demonstrates that SMAD1 can interact with YAP1 to enhance the DDP resistance of GC cells.
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Affiliation(s)
- Wanjing Chen
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Jingtao Hu
- Department of Aviation Health, Anhui Branch of China Eastern Airlines Co. LTD, Hefei, 230012, Anhui, People's Republic of China
| | - Yawei He
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Liang Yu
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Yanwei Liu
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Yusheng Cheng
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Benli Jia
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China
| | - Xianghua Li
- Department of Molecular Pathology, Hefei Da'an Medical Laboratory Co., LTD, Hefei, 230012, Anhui, People's Republic of China
| | - Gang Yu
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China.
| | - Yong Wang
- Department of General Surgery, The Second Hospital of Anhui Medical University, No. 678, Furong Road, Economic and Technological Development District, Hefei, 230601, Anhui, People's Republic of China.
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19
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Guo X, Chang M, Wang Y, Xing B, Ma W. B7-H3 in Brain Malignancies: Immunology and Immunotherapy. Int J Biol Sci 2023; 19:3762-3780. [PMID: 37564196 PMCID: PMC10411461 DOI: 10.7150/ijbs.85813] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/13/2023] [Indexed: 08/12/2023] Open
Abstract
The immune checkpoint B7-H3 (CD276), a member of the B7 family with immunoregulatory properties, has been identified recently as a novel target for immunotherapy for refractory blood cancers and solid malignant tumors. While research on B7-H3 in brain malignancies is limited, there is growing interest in exploring its therapeutic potential in this context. B7-H3 plays a crucial role in regulating the functions of immune cells, cancer-associated fibroblasts, and endothelial cells within the tumor microenvironment, contributing to the creation of a pro-tumorigenic milieu. This microenvironment promotes uncontrolled cancer cell proliferation, enhanced metabolism, increased cancer stemness, and resistance to standard treatments. Blocking B7-H3 and terminating its immunosuppressive function is expected to improve anti-tumor immune responses and, in turn, ameliorate the progression of tumors. Results from preclinical or observative studies and early-phase trials targeting B7-H3 have revealed promising anti-tumor efficacy and acceptable toxicity in glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, neuroblastoma, craniopharyngioma, atypical teratoid/rhabdoid tumor, and brain metastases. Ongoing clinical trials are now investigating the use of CAR-T cell therapy and antibody-drug conjugate therapy, either alone or in combination with standard treatments or other therapeutic approaches, targeting B7-H3 in refractory or recurrent GBMs, DIPGs, neuroblastomas, medulloblastomas, ependymomas, and metastatic brain tumors. These trials hold promise for providing effective treatment options for these challenging intracranial malignancies in both adult and pediatric populations.
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Affiliation(s)
- Xiaopeng Guo
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mengqi Chang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yu Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Bing Xing
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Wenbin Ma
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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20
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Rasic P, Jeremic M, Jeremic R, Dusanovic Pjevic M, Rasic M, Djuricic SM, Milickovic M, Vukadin M, Mijovic T, Savic D. Targeting B7-H3-A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment. Molecules 2023; 28:molecules28083356. [PMID: 37110590 PMCID: PMC10145344 DOI: 10.3390/molecules28083356] [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: 03/14/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.
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Affiliation(s)
- Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Marija Jeremic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Rada Jeremic
- Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Marija Dusanovic Pjevic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milica Rasic
- Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Slavisa M Djuricic
- Department of Clinical Pathology, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and Herzegovina
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Miroslav Vukadin
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Tanja Mijovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
| | - Djordje Savic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia "Dr. Vukan Cupic", 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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21
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Overview of the miR-29 family members' function in breast cancer. Int J Biol Macromol 2023; 230:123280. [PMID: 36652981 DOI: 10.1016/j.ijbiomac.2023.123280] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 12/02/2022] [Accepted: 01/07/2023] [Indexed: 01/17/2023]
Abstract
Accumulating evidence has indicated the importance of microRNAs (miRs) in the biology of human malignancies by targeting multiple signaling pathways and different Messenger RNA transcripts. Despite conflicting information and controversial roles in diverse cancers, miR-29 has been mostly characterized as a tumor suppressor in breast cancer (BC). Several signaling axes, including TIMP3/STAT1/FOXO1, GATA3-miR-29b, and EZH2-miR-29b/miR-30d-LOXL4 are controlled, at least partially, by miR-29 family members to suppress proliferation, invasion, and metastasis of BC cells. In contrast, some other studies showed that miR-29 is notably elevated in the serum/tissue of BC patients and triggers migration and metastasis by targeting various genes and transcription factors such as tristetraprolin, N-myc interactor, and ten-eleven translocation 1. This disagreement can be explained by the fact that miR-29 family members have a variety of regulatory roles depending on their environment and signaling pathways. Long non-coding RNAs also can modulate miR-29 expression in BC. We summarized recent discoveries regarding the important value of the miR-29 family in BC, focusing on the effects of miR-29 up/down-regulation in different subtypes of BC. We also explored the effects of miR-29 in BC initiation and progression, invasion, and therapy resistance.
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22
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Montoyo-Pujol YG, García-Escolano M, Ponce JJ, Delgado-García S, Martín TA, Ballester H, Castellón-Molla E, Martínez-Peinado P, Pascual-García S, Sempere-Ortells JM, Peiró G. Variable Intrinsic Expression of Immunoregulatory Biomarkers in Breast Cancer Cell Lines, Mammospheres, and Co-Cultures. Int J Mol Sci 2023; 24:4478. [PMID: 36901916 PMCID: PMC10003642 DOI: 10.3390/ijms24054478] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/13/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Advances in immunotherapy have increased interest in knowing the role of the immune system in breast cancer (BC) pathogenesis. Therefore, immune checkpoints (IC) and other pathways related to immune regulation, such as JAK2 and FoXO1, have emerged as potential targets for BC treatment. However, their intrinsic gene expression in vitro has not been extensively studied in this neoplasia. Thus, we evaluated the mRNA expression of tumor-cell-intrinsic CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3), JAK2, and FoXO1 in different BC cell lines, derived mammospheres, and co-cultures with peripheral blood mononuclear cells (PBMCs) by real-time quantitative polymerase chain reaction (qRT-PCR). Our results showed that intrinsic CTLA-4, CD274 (PD-L1), and PDCD1LG2 (PD-L2) were highly expressed in triple-negative cell lines, while CD276 was predominantly overexpressed in luminal cell lines. In contrast, JAK2 and FoXO1 were under-expressed. Moreover, high levels of CTLA-4, PDCD1 (PD1), CD274 (PD-L1), PDCD1LG2 (PD-L2), and JAK2 were found after mammosphere formation. Finally, the interaction between BC cell lines and peripheral blood mononuclear cells (PBMCs) stimulates the intrinsic expression of CTLA-4, PCDC1 (PD1), CD274 (PD-L1), and PDCD1LG2 (PD-L2). In conclusion, the intrinsic expression of immunoregulatory genes seems very dynamic, depending on BC phenotype, culture conditions, and tumor-immune cell interactions.
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Affiliation(s)
- Yoel Genaro Montoyo-Pujol
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Medical Oncology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Marta García-Escolano
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - José J. Ponce
- Medical Oncology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Silvia Delgado-García
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Tina Aurora Martín
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Hortensia Ballester
- Gynecology and Obstetrics Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Castellón-Molla
- Pathology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Pascual Martínez-Peinado
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
| | - Sandra Pascual-García
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
| | - José Miguel Sempere-Ortells
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Gloria Peiró
- Research Unit, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Pathology Department, Dr. Balmis University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
- Biotechnology Department, Immunology Division, University of Alicante, Ctra San Vicente s/n., 03080 San Vicente del Raspeig, Spain
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23
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Li HX, Wang SQ, Lian ZX, Deng SL, Yu K. Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer. Cells 2022; 12:cells12010064. [PMID: 36611857 PMCID: PMC9818185 DOI: 10.3390/cells12010064] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.
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Affiliation(s)
- Huan-Xiang Li
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shu-Qi Wang
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Zheng-Xing Lian
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Shou-Long Deng
- National Health Commission (NHC) of China Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
- Correspondence: (S.-L.D.); (K.Y.)
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
- Correspondence: (S.-L.D.); (K.Y.)
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24
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Yi X, Hu W. Advances in adoptive cellular therapy for colorectal cancer: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1404. [PMID: 36660664 PMCID: PMC9843349 DOI: 10.21037/atm-22-6196] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/19/2022] [Indexed: 01/01/2023]
Abstract
Background and Objective In recent years, adoptive cell therapy (ACT) has shown great potential in antitumor treatment. To significantly improve the clinical efficacy of ACT against solid tumors, we may need to carefully study the latest developments in ACT. As one of the most common malignancies, colorectal cancer (CRC) is a major risk to human health and has become a significant burden on global healthcare systems. This article reviews the recent advances in the treatment of CRC with ACT. Methods We searched PubMed for articles related to ACT for CRC published as of August 31, 2022, and retrieved relevant clinical trial information on the National Institutes of Health ClinicalTrials.gov website. Based on search results, comprehensive and systematic review is made. Key Content and Findings This article provides an overview of the research progress of ACT for CRC, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR)-engineered T-cell therapy, and tumor-infiltrating lymphocyte (TIL) therapy. Common tumor-associated antigens (TAAs) in clinical trials of CAR-T cell therapy for CRC are described. Conclusions Despite many obstacles, ACT shows great promise in treating CRC. Therefore, more basic experimental studies and clinical trials are warranted to further clarify the effectiveness and safety of ACT.
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Affiliation(s)
- Xing Yi
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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25
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Therachiyil L, Hussein OJ, Uddin S, Korashy HM. Regulation of the aryl hydrocarbon receptor in cancer and cancer stem cells of gynecological malignancies: An update on signaling pathways. Semin Cancer Biol 2022; 86:1186-1202. [PMID: 36252938 DOI: 10.1016/j.semcancer.2022.10.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 10/04/2022] [Accepted: 10/12/2022] [Indexed: 01/27/2023]
Abstract
Gynecological malignancies are a female type of cancers that affects the reproductive system. Cancer metastasis or recurrence mediated by cellular invasiveness occurs at advanced stages of cancer progression. Cancer Stem Cells (CSCs) enrichment in tumors leads to chemoresistance, which results in cancer mortality. Exposure to environmental pollutants such as polycyclic aromatic hydrocarbons is associated with an increased the risk of CSC enrichment in gynecological cancers. One of the important pathways that mediates the metabolism and bioactivation of these environmental chemicals is the transcription factor, aryl hydrocarbon receptor (AhR). The present review explores the molecular mechanisms regulating the crosstalk and interaction of the AhR with cancer-related signaling pathways, such as apoptosis, epithelial-mesenchymal transition, immune checkpoints, and G-protein-coupled receptors in several gynecological malignancies such as ovarian, uterine, endometrial, and cervical cancers. The review also discusses the potential of targeting the AhR pathway as a novel chemotherapy for gynecological cancers.
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Affiliation(s)
- Lubna Therachiyil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Ola J Hussein
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
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26
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Wang J, Luo Z, Lin L, Sui X, Yu L, Xu C, Zhang R, Zhao Z, Zhu Q, An B, Wang Q, Chen B, Leung ELH, Wu Q. Anoikis-Associated Lung Cancer Metastasis: Mechanisms and Therapies. Cancers (Basel) 2022; 14:cancers14194791. [PMID: 36230714 PMCID: PMC9564242 DOI: 10.3390/cancers14194791] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 12/08/2022] Open
Abstract
Simple Summary Anoikis is a programmed cell death process resulting from the loss of interaction between cells and the extracellular matrix. Therefore, it is necessary to overcome anoikis when tumor cells acquire metastatic potential. In lung cancer, the composition of the extracellular matrix, cell adhesion-related membrane proteins, cytoskeletal regulators, and epithelial–mesenchymal transition are involved in the process of anoikis, and the initiation of apoptosis signals is a critical step in anoikis. Inversely, activation of growth signals counteracts anoikis. This review summarizes the regulators of lung cancer-related anoikis and explores potential drug applications targeting anoikis. Abstract Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it inhibits the escape of tumor cells from the native extracellular matrix to other organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat lung cancer. Several natural and synthetic products exhibit the pro-anoikis potential in lung cancer cells and in vivo models. These products include artonin E, imperatorin, oroxylin A, lupalbigenin, sulforaphane, renieramycin M, avicequinone B, and carbenoxolone. This review summarizes the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in lung cancer metastasis and discusses the therapeutic potential of targeting anoikis in the treatment of lung cancer metastasis.
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Affiliation(s)
- Jing Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Zhijie Luo
- The First Clinical Medical College, The First Hospital Affiliated, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Lizhu Lin
- The First Clinical Medical College, The First Hospital Affiliated, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinbing Sui
- School of Pharmacy, Department of Medical Oncology, Hangzhou Normal University, Hangzhou 311121, China
| | - Lili Yu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Cong Xu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Ruonan Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Ziming Zhao
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qianru Zhu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Bo An
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qiao Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Bi Chen
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Elaine Lai-Han Leung
- Cancer Center, Faculty of Health Science, MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau 999078, China
- Correspondence: (E.L.-H.L.); (Q.W.)
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong University of Technology, Guangzhou 510006, China
- Zhuhai MUST Science and Technology Research Institute, Zhuhai 519031, China
- Correspondence: (E.L.-H.L.); (Q.W.)
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27
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Li Y, Cai Q, Shen X, Chen X, Guan Z. Overexpression of B7-H3 Is Associated With Poor Prognosis in Laryngeal Cancer. Front Oncol 2021; 11:759528. [PMID: 34938657 PMCID: PMC8685272 DOI: 10.3389/fonc.2021.759528] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/12/2021] [Indexed: 01/01/2023] Open
Abstract
The immune checkpoint molecule, B7-H3, which belongs to the B7 family, has been shown to be overexpressed in various cancers. Its role in tumors is not well defined, and many studies suggest that it is associated with poor clinical outcomes. The effect of B7-H3 on laryngeal cancer has not been reported. This study investigated the expression of B7-H3 in laryngeal squamous cell carcinoma (LSCC), and its relationship with clinicopathological factors and prognosis of LSCC patients. The gene expression quantification data and clinical data of LSCC retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were analyzed to determine the diagnostic and prognostic roles of B7-H3. Quantitative real-time polymerase chain reaction (qRT-PCR) was then performed to determine the gene expression level of B7-H3 between LSCC tissues and paired normal adjacent tissues. In addition, TCGA RNA-seq data was analyzed to evaluate the expression level of B7 family genes. Next, the protein expression of B7-H3 and CD8 in LSCC was determined using immunohistochemistry and immunofluorescence. qRT-PCR results showed that the expression level of B7-H3 mRNA was significantly higher in LSCC tissues than in adjacent normal tissues. Similar results were obtained from the TCGA analysis. The expression of B7-H3 was significantly associated with T stage, lymph node metastasis, and pathological tumor node metastasis (TNM) stage, and it was also an independent factor influencing the overall survival time (OS) of patients with LSCC. In addition, B7-H3 was negatively correlated with CD8+T cells. These results show that B7-H3 is upregulated in LSCC. Therefore, B7-H3 may serve as a biomarker of poor prognosis and a promising therapeutic target in LSCC.
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Affiliation(s)
- Yixuan Li
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qian Cai
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ximing Shen
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoting Chen
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhong Guan
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Zhong Guan,
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28
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Vuletić A, Mirjačić Martinović K, Tišma Miletić N, Zoidakis J, Castellvi-Bel S, Čavić M. Cross-Talk Between Tumor Cells Undergoing Epithelial to Mesenchymal Transition and Natural Killer Cells in Tumor Microenvironment in Colorectal Cancer. Front Cell Dev Biol 2021; 9:750022. [PMID: 34858978 PMCID: PMC8631470 DOI: 10.3389/fcell.2021.750022] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/14/2021] [Indexed: 12/19/2022] Open
Abstract
Tumor cells undergoing epithelial to mesenchymal transition (EMT) and immune cells in tumor microenvironment (TME) reciprocally influence each other. Immune cells, by supplying TME with bioactive molecules including cytokines, chemokines, enzymes, metabolites, and by physical interactions with tumor cells via their receptors, represent an important factor that affects EMT. Chronical inflammation in TME favorizes tumor growth and invasiveness and stimulates synthesis of EMT promoting transcription factors. Natural killer (NK) cells, owing to their unique ability to exert cytotoxic function independent of major histocompatibility (MHC)-mediated antigen presentation, play a significant role in the control of metastasis in colorectal cancer (CRC). Although, the cross-talk between immune cells and tumor cells in general favors the induction of EMT and inhibition of antitumor immune responses, there are some changes in the immunogenicity of tumor cells during EMT of CRC cells that increase their susceptibility to NK cell cytotoxic lysis. However, suppressive TME downmodulates the expression of activating NK cell receptors, decreases the expression of activating and increases the expression of inhibitory NK cell ligands on tumor cells, and impairs NK cell metabolism that altogether negatively affects the overall NK cell function. Furthermore, process of EMT is often associated with increased expression of programmed cell death ligand (PD-L) and expression of immune checkpoint molecules PD-1, TIGIT, and TIM3 on functionally exhausted NK cells in TME in CRC. In this review we discuss modalities of cross-talk between tumor cells and NK cells, with regard of EMT-driven changes.
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Affiliation(s)
- Ana Vuletić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | | | - Nevena Tišma Miletić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Jerome Zoidakis
- Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Sergi Castellvi-Bel
- Gastroenterology Department, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomčdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Milena Čavić
- Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
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29
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Feng R, Chen Y, Liu Y, Zhou Q, Zhang W. The role of B7-H3 in tumors and its potential in clinical application. Int Immunopharmacol 2021; 101:108153. [PMID: 34678689 DOI: 10.1016/j.intimp.2021.108153] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
B7-H3 (CD276 molecule) is an immune checkpoint from the B7 family of molecules that acts more as a co-inhibitory molecule to promote tumor progression. It is abnormally expressed on tumor cells and can be induced to express on antigen-presenting cells (APCs) including dendritic cells (DCs) and macrophages. In the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing T cell response, promoting the polarization of tumor-associated macrophages (TAMs) to M2, inhibiting the function of DCs, and promoting the migration and invasion of cancer-associated fibroblasts (CAFs). In addition, through non-immunological functions, B7-H3 promotes tumor cell proliferation, invasion, metastasis, resistance, angiogenesis, and metabolism, or in the form of exosomes to promote tumor progression. In this process, microRNAs can regulate the expression of B7-H3. B7-H3 may serve as a potential biomarker for tumor diagnosis and a marker of poor prognosis. Immunotherapy targeting B7-H3 and the combination of B7-H3 and other immune checkpoints have shown certain efficacy. In this review, we summarized the basic characteristics of B7-H3 and its mechanism to promote tumor progression by inducing immunosuppression and non-immunological functions, as well as the potential clinical applications of B7-H3 and immunotherapy based on B7-H3.
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Affiliation(s)
- Ranran Feng
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Liu
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qing Zhou
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Wenling Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
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30
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Lin W, Xu Y, Gao J, Zhang H, Sun Y, Qiu X, Huang Q, Kong L, Lu JJ. Multi-Omics Data Analyses Identify B7-H3 as a Novel Prognostic Biomarker and Predict Response to Immune Checkpoint Blockade in Head and Neck Squamous Cell Carcinoma. Front Immunol 2021; 12:757047. [PMID: 34675936 PMCID: PMC8524082 DOI: 10.3389/fimmu.2021.757047] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/16/2021] [Indexed: 11/24/2022] Open
Abstract
B7 homolog 3 (B7-H3) is a recently found superfamily B7 molecule and therefore has significant involvement in immunological regulation. However, the relationships of B7-H3 expression with the tumor microenvironment (TME), response to immunotherapy, and prognosis in head and neck squamous cell carcinoma (HNSCC) are still unknown. In the present analysis, we determined B7-H3 as a novel biomarker that predicts the prognosis and response to immunotherapy in HNSCC. B7-H3 expression is enhanced in HNSCC compared to normal sample and is stably expressed in HNSCC cell line. Besides, high B7-H3 expression is correlated with a dismal prognosis and resistance to immunotherapy and contributes to an immunosuppressive microenvironment. Moreover, single-cell RNA sequencing (scRNA-seq) analysis shows that B7-H3 is mainly expressed in the stromal as well as malignant cells. In conclusion, the study provides insight in understanding the prognostic value of B7-H3 in HNSCC and highlights its involvement in promoting the immunosuppressive microenvironment, which presents an attractive strategy for antibody-based immunotherapy.
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Affiliation(s)
- Wanzun Lin
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Yanyan Xu
- Department of Gynaecology and Obstetrics, Shanghai Jiangqiao Hospital, Shanghai, China
| | - Jing Gao
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Haojiong Zhang
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Yun Sun
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Xianxin Qiu
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Qingting Huang
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
| | - Lin Kong
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Jiade J Lu
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
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31
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Kanayama T, Miyachi M, Sugimoto Y, Yagyu S, Kikuchi K, Tsuchiya K, Iehara T, Hosoi H. Reduced B7-H3 expression by PAX3-FOXO1 knockdown inhibits cellular motility and promotes myogenic differentiation in alveolar rhabdomyosarcoma. Sci Rep 2021; 11:18802. [PMID: 34552155 PMCID: PMC8458399 DOI: 10.1038/s41598-021-98322-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 09/07/2021] [Indexed: 11/09/2022] Open
Abstract
B7-H3 (also known as CD276) is associated with aggressive characteristics in various cancers. Meanwhile, in alveolar rhabdomyosarcoma (ARMS), PAX3-FOXO1 fusion protein is associated with increased aggressiveness and poor prognosis. In the present study, we explored the relationship between PAX3-FOXO1 and B7-H3 and the biological roles of B7-H3 in ARMS. Quantitative real time PCR and flow cytometry revealed that PAX3-FOXO1 knockdown downregulated B7-H3 expression in all the selected cell lines (Rh-30, Rh-41, and Rh-28), suggesting that PAX3-FOXO1 positively regulates B7-H3 expression. Gene expression analysis revealed that various genes and pathways involved in chemotaxis, INF-γ production, and myogenic differentiation were commonly affected by the knockdown of PAX3-FOXO1 and B7-H3. Wound healing and transwell migration assays revealed that both PAX3-FOXO1 and B7-H3 were associated with cell migration. Furthermore, knockdown of PAX3-FOXO1 or B7-H3 induced myogenin expression in all cell lines, although myosin heavy chain induction varied depending on the cellular context. Our results indicate that PAX3-FOXO1 regulates B7-H3 expression and that PAX3-FOXO1 and B7-H3 are commonly associated with multiple pathways related to an aggressive phenotype in ARMS, such as cell migration and myogenic differentiation block.
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Affiliation(s)
- Takuyo Kanayama
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mitsuru Miyachi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Yohei Sugimoto
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shigeki Yagyu
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ken Kikuchi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kunihiko Tsuchiya
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomoko Iehara
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hajime Hosoi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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32
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Huang L, Zhou Y, Sun Q, Cao L, Zhang X. Evaluation of the role of soluble B7-H3 in association with membrane B7-H3 expression in gastric adenocarcinoma. Cancer Biomark 2021; 33:123-129. [PMID: 34459388 DOI: 10.3233/cbm-210178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVE Gastric adenocarcinoma (GAC) is one of the most common malignancies. Increasing data have indicated a correlation between soluble B7-H3 (sB7-H3) levels and tumor malignancies. In this study, we aim to investigate the level of soluble B7-H3 in serum of GAC patients. Further, we analyze the correlation between sB7-H3 level and tissue B7-H3 expression and explore the clinical evaluation value of sB7-H3 associated with pathological characteristics and prognosis of GAC patients. METHODS One hundred and twenty-eight serum and tissue samples of GAC 20 serum and tissue samples of gastritis patients and 77 serum, 5 tissue samples of healthy controls were collected. The serum levels of sB7-H3 were detected by Enzyme-linked immunosorbent assay (ELISA), while the expression of membrane B7-H3 (mB7-H3) and Ki67 were evaluated by immunohistochemistry. The correlation between sB7-H3 and mB7-H3, sB7-H3 and Ki67, sB7-H3 or mB7-H3 and clinical features were analyzed by Pearson's Chi-square test. RESULTS Both serum level of sB7-H3 and tissue B7-H3 of GAC patients were significantly higher than those of gastritis patients and healthy controls. sB7-H3 level was correlated with total B7-H3 expression in tissues (r= 0.2801, P= 0.0014). Notably, the concentration of sB7-H3 was correlated with its expression of membrane form in tumor cells (r= 0.3251, P= 0.002) while not in stromal cells (r= 0.07676, P= 0.3891). Moreover, the levels of sB7-H3 in patients with TNM stage III/IV or with Infiltration depth T3/T4 or with lymph node metastasis were significantly higher than those of patients with TNM stage I/II (P= 0.0020) or with Infiltration depth T1/T2 (P= 0.0169) or with no lymph node metastasis (P= 0.0086). Tumor B7-H3 score, but not stromal B7-H3 score, in patients with TNM stage III/IV or with lymph node metastasis was significantly higher than those with TNM stage I/II (P= 0.0150) or with no lymph node metastasis (P= 0.182). CONCLUSIONS Soluble B7-H3 level may reflect the tissue B7-H3 expression on tumor cells of GAC tissues. Elevated level of sB7-H3 in serum suggests poor clinical pathological characteristics of GAC patients.
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Affiliation(s)
- Lili Huang
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yan Zhou
- The AoYang Cancer Research Institute of Jiangsu University, Zhangjiagang, Suzhou, Jiangsu, China.,Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Qiuwei Sun
- The AoYang Cancer Research Institute of Jiangsu University, Zhangjiagang, Suzhou, Jiangsu, China
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Suzhou, Jiangsu, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Suzhou, Jiangsu, China
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33
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Rasic P, Jovanovic-Tucovic M, Jeremic M, Djuricic SM, Vasiljevic ZV, Milickovic M, Savic D. B7 homologue 3 as a prognostic biomarker and potential therapeutic target in gastrointestinal tumors. World J Gastrointest Oncol 2021; 13:799-821. [PMID: 34457187 PMCID: PMC8371522 DOI: 10.4251/wjgo.v13.i8.799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 04/19/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
The most common digestive system (DS) cancers, including tumors of the gastrointestinal tract (GIT) such as colorectal cancer (CRC), gastric cancer (GC) and esophageal cancer (EC) as well as tumors of DS accessory organs such as pancreatic and liver cancer, are responsible for more than one-third of all cancer-related deaths worldwide, despite the progress that has been achieved in anticancer therapy. Due to these limitations in treatment strategies, oncological research has taken outstanding steps towards a better understanding of cancer cell biological complexity and heterogeneity. These studies led to new molecular target-driven therapeutic approaches. Different in vivo and in vitro studies have revealed significant expression of B7 homologue 3 (B7-H3) among the most common cancers of the GIT, including CRC, GC, and EC, whereas B7-H3 expression in normal healthy tissue of these organs was shown to be absent or minimal. This molecule is able to influence the biological behavior of GIT tumors through the various immunological and nonimmunological molecular mechanisms, and some of them are shown to be the result of B7-H3-related induction of signal transduction pathways, such as Janus kinase 2/signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, and nuclear factor-κB. B7-H3 exerts an important role in progression, metastasis and resistance to anticancer therapy in these tumors. In addition, the results of many studies suggest that B7-H3 stimulates immune evasion in GIT tumors by suppressing antitumor immune response. Accordingly, it was observed that experimental depletion or inhibition of B7-H3 in gastrointestinal cancers improved antitumor immune response, impaired tumor progression, invasion, angiogenesis, and metastasis and decreased resistance to anticancer therapy. Finally, the high expression of B7-H3 in most common cancers of the GIT was shown to be associated with poor prognosis. In this review, we summarize the established data from different GIT cancer-related studies and suggest that the B7-H3 molecule could be a promising prognostic biomarker and therapeutic target for anticancer immunotherapy in these tumors.
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Affiliation(s)
- Petar Rasic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
| | - Maja Jovanovic-Tucovic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
| | - Marija Jeremic
- Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
| | - Slavisa M Djuricic
- Department of Clinical Pathology, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
- Faculty of Medicine, University of Banja Luka, Banja Luka 78 000, Bosnia and Herzegovina
| | - Zorica V Vasiljevic
- Department of Clinical Microbiology, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
| | - Maja Milickovic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
- School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
| | - Djordje Savic
- Department of Abdominal Surgery, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic“, Belgrade 11 000, Serbia
- School of Medicine, University of Belgrade, Belgrade 11 000, Serbia
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34
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Zhou WT, Jin WL. B7-H3/CD276: An Emerging Cancer Immunotherapy. Front Immunol 2021; 12:701006. [PMID: 34349762 PMCID: PMC8326801 DOI: 10.3389/fimmu.2021.701006] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.
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Affiliation(s)
- Wu-Tong Zhou
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Lin Jin
- Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai, China.,Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
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35
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Michelakos T, Kontos F, Barakat O, Maggs L, Schwab JH, Ferrone CR, Ferrone S. B7-H3 targeted antibody-based immunotherapy of malignant diseases. Expert Opin Biol Ther 2021; 21:587-602. [PMID: 33301369 PMCID: PMC8087627 DOI: 10.1080/14712598.2021.1862791] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
Introduction: Recent advances in immuno-oncology and bioengineering have rekindled the interest in monoclonal antibody (mAb)-based immunotherapies for malignancies. Crucial for their success is the identification of tumor antigens (TAs) that can serve as targets. B7-H3, a member of the B7 ligand family, represents such a TA. Although its exact functions and receptor(s) remain unclear, B7-H3 has predominantly a pro-tumorigenic effect mainly by suppressing the anti-tumor functions of T-cells.Areas covered: Initially we present a historical perspective on TA-specific antibodies for diagnosis and treatment of malignancies. Following a description of the TA requirements to be an attractive antibody-based immunotherapy target, we show that B7-H3 fulfills these criteria. We discuss its structure and functions. In a review and pooled analysis, we describe the limited B7-H3 expression in normal tissues and estimate B7-H3 expression frequency in tumors, tumor-associated vasculature and cancer initiating cells (CICs). Lastly, we discuss the association of B7-H3 expression in tumors with poor prognosis.Expert opinion: B7-H3 is an attractive target for mAb-based cancer immunotherapy. B7-H3-targeting strategies are expected to be highly effective and - importantly - safe. To fully exploit the diagnostic and therapeutic potential of B7-H3, its expression in pre-malignant lesions, serum, metastases, and CICs requires further investigation.
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Affiliation(s)
- Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Omar Barakat
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Luke Maggs
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Joseph H Schwab
- Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
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Marcucci F, Rumio C. Depleting Tumor Cells Expressing Immune Checkpoint Ligands-A New Approach to Combat Cancer. Cells 2021; 10:872. [PMID: 33921301 PMCID: PMC8069236 DOI: 10.3390/cells10040872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/02/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022] Open
Abstract
Antibodies against inhibitory immune checkpoint molecules (ICPMs), referred to as immune checkpoint inhibitors (ICIs), have gained a prominent place in cancer therapy. Several ICIs in clinical use have been engineered to be devoid of effector functions because of the fear that ICIs with preserved effector functions could deplete immune cells, thereby curtailing antitumor immune responses. ICPM ligands (ICPMLs), however, are often overexpressed on a sizeable fraction of tumor cells of many tumor types and these tumor cells display an aggressive phenotype with changes typical of tumor cells undergoing an epithelial-mesenchymal transition. Moreover, immune cells expressing ICPMLs are often endowed with immunosuppressive or immune-deviated functionalities. Taken together, these observations suggest that compounds with the potential of depleting cells expressing ICPMLs may become useful tools for tumor therapy. In this article, we summarize the current state of the art of these compounds, including avelumab, which is the only ICI targeting an ICPML with preserved effector functions that has gained approval so far. We also discuss approaches allowing to obtain compounds with enhanced tumor cell-depleting potential compared to native antibodies. Eventually, we propose treatment protocols that may be applied in order to optimize the therapeutic efficacy of compounds that deplete cells expressing ICPMLs.
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Affiliation(s)
- Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, 20134 Milan, Italy;
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Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs. Cancers (Basel) 2021; 13:cancers13071674. [PMID: 33918136 PMCID: PMC8037840 DOI: 10.3390/cancers13071674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/05/2021] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary This review provides a critical overview of the state of the art of the characterization of the immunological profile of a rare component of the tumors, denominated cancer stem cells (CSCs) or cancer initiating cells (CICs). These cells are endowed with the ability to form and propagate tumors and resistance to therapies, including the most innovative approaches. These investigations contribute to understanding the mechanisms regulating the interaction of CSCs/CICs with the immune system and identifying novel therapeutic approaches to render these cells visible and susceptible to immune responses. Abstract Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.
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The expression of B7-H3 isoforms in newly diagnosed glioblastoma and recurrence and their functional role. Acta Neuropathol Commun 2021; 9:59. [PMID: 33795013 PMCID: PMC8017683 DOI: 10.1186/s40478-021-01167-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/21/2021] [Indexed: 01/01/2023] Open
Abstract
Short survival of glioblastoma (GBM) patients is due to systematic tumor recurrence. Our laboratory identified a GBM cell subpopulation able to leave the tumor mass (TM) and invade the subventricular zone (SVZ-GBM cells). SVZ-GBM cells escape treatment and appear to contribute to GBM recurrence. This study aims to identify proteins specifically expressed by SVZ-GBM cells and to define their role(s) in GBM aggressiveness and recurrence. The proteome was compared between GBM cells located in the initial TM and SVZ-GBM cells using mass spectrometry. Among differentially expressed proteins, we confirmed B7-H3 by western blot (WB) and quantitative RT-PCR. B7-H3 expression was compared by immunohistochemistry and WB (including expression of its isoforms) between human GBM (N = 14) and non-cancerous brain tissue (N = 8), as well as newly diagnosed GBM and patient-matched recurrences (N = 11). Finally, the expression of B7-H3 was modulated with short hairpin RNA and/or over-expression vectors to determine its functional role in GBM using in vitro assays and a xenograft mouse model of GBM. B7-H3 was a marker for SVZ-GBM cells. It was also increased in human GBM pericytes, myeloid cells and neoplastic cells. B7-H3 inhibition in GBM cells reduced their tumorigenicity. Out of the two B7-H3 isoforms, only 2IgB7-H3 was detected in non-cancerous brain tissue, whereas 4IgB7-H3 was specific for GBM. 2IgB7-H3 expression was higher in GBM recurrences and increased resistance to temozolomide-mediated apoptosis. To conclude, 4IgB7-H3 is an interesting candidate for GBM targeted therapies, while 2IgB7-H3 could be involved in recurrence through resistance to chemotherapy.
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Hu X, Xu M, Hu Y, Li N, Zhou L. B7-H3, Negatively Regulated by miR-128, Promotes Colorectal Cancer Cell Proliferation and Migration. Cell Biochem Biophys 2021; 79:397-405. [PMID: 33743142 DOI: 10.1007/s12013-021-00975-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 03/05/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND B7 homolog 3 (B7-H3), a member of the immunoregulatory ligand B7 family, is pivotal in T-cell-mediated immune response. It is widely expressed in diverse human tumors and its high expression indicates the poor prognosis of the patients. Nonetheless, B7-H3's role in colorectal cancer (CRC) needs to be further explored. METHODS Western blot and immunohistochemistry were employed for detecting B7-H3 protein expression in CRC tissues and cell lines, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for detecting B7-H3 mRNA and miR-128 expression levels. CRC cell lines SW620 and HT29 were used to construct B7-H3 overexpression or knockdown cell models, respectively. Cell counting kit-8 (CCK-8), 5-bromo-2'-deoxyuridine (BrdU), and scratch wound healing assays were employed for evaluating the effects of B7-H3 on CRC cell multiplication and migration. Besides, the regulatory relationship between miR-128 and B7-H3 was validated through dual-luciferase reporter gene assay, qRT-PCR, and western blotting. RESULTS B7-H3 expression level was remarkably elevated in CRC tissues and cell lines, and its high expression level was associated with increased tumor size, positive lymph node metastasis, and increased T stage. In CRC cells, B7-H3 overexpression significantly facilitated the cell multiplication and migration, while B7-H3 knockdown worked oppositely. Moreover, B7-H3 was identified as a target of miR-128, and miR-128 negatively regulated B7-H3 expression in CRC cells. CONCLUSION B7-H3 expression is upregulated in CRC tissues and cell lines, and B7-H3 participates in promoting the proliferation and migration of CRC cells. Besides, B7-H3 expression is negatively regulated by miR-128 in CRC.
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Affiliation(s)
- Xiaomao Hu
- Department of Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China.
- Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China.
| | - Minxian Xu
- Department of Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Yangzhi Hu
- Department of Gastroenterology Surgery, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Na Li
- Department of Oncology, Affiliated Hospital of Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Lei Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
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Zhang C, Chen Y, Li F, Yang M, Meng F, Zhang Y, Chen W, Wang W. B7-H3 is spliced by SRSF3 in colorectal cancer. Cancer Immunol Immunother 2021; 70:311-321. [PMID: 32719950 PMCID: PMC10991627 DOI: 10.1007/s00262-020-02683-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
Abstract
B7-H3, an important co-inhibitor, is abnormally highly expressed in a variety of malignancies. The antibodies targeting B7-H3 have exhibited beneficial therapeutic effects in clinical trials. Therefore, discovery of the regulatory factors in B7-H3 expression may provide new strategies for tumor therapy. Here, we investigated the splicing factors involved in the splicing of B7-H3. By individual knockdown of the splicing factors in colorectal cancer (CRC) cells, we found that B7-H3 expression was markedly inhibited by SRSF3 and SRSF8, especially SRSF3. Then we found that both SRSF3 and B7-H3 were highly expressed in CRC tissues. Moreover, high-expression of either SRSF3 or B7-H3 was significantly correlated with poor prognosis of patients. The expression of B7-H3 mRNA and protein were evidently reduced by SRSF3 silence, but were enhanced by overexpression of SRSF3 in both HCT-116 and HCT-8 cells. The results from the RNA immunoprecipitation (RIP) assays demonstrated that SRSF3 protein directly binds to B7-H3 mRNA. In addition, we constructed a minigene recombinant plasmid for expressing B7-H3 exons 3-6. We found that SRSF3 contributed to the retention of B7-H3 exon 4. These findings demonstrate that SRSF3 involves in the splicing of B7-H3 by directly binding to its exon 4 and/or 6. It may provide novel insights into the regulatory mechanisms of B7-H3 expression and potential strategies for the treatment of CRC.
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Affiliation(s)
- Chunxia Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yinshuang Chen
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Fuchao Li
- Department of Gerontology, The Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Fanyi Meng
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Yawen Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Weichang Chen
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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Shrestha R, Bridle KR, Crawford DHG, Jayachandran A. Immune checkpoint molecules are regulated by transforming growth factor (TGF)- β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma. Int J Med Sci 2021; 18:2466-2479. [PMID: 34104078 PMCID: PMC8176170 DOI: 10.7150/ijms.54239] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a high mortality rate. Epithelial-to-mesenchymal transition (EMT) confers cancer cells with immune evasive ability by modulating the expression of immune checkpoints in many cancers. Thus, the aim of our study is to examine the interplay between EMT and immune checkpoint molecules in HCC. A reversible EMT model was utilised with transforming growth factor (TGF)-β1 as an EMT inducer for HCC cell lines Hep3B and PLC/PRF/5. HCC cells were treated with TGF-β1 for 72 h and the EMT status and immune checkpoint expression were examined. In addition, the migratory ability of HCC cells were examined using wound healing and transwell migration assays in the reversible EMT model. siRNA-mediated knockdown of immune checkpoint molecule, B7-H3, was further utilised to validate the association between TGF-β1-mediated EMT and immune checkpoint expression in HCC. In addition, a web-based platform, SurvExpress, was utilised to evaluate the association between expression of TGF-β1 in combination with immune checkpoint molecules and overall survival in HCC patients. We observed induction of EMT upon treatment of HCC cells with TGF-β1 revealed by reduced expression of epithelial markers along with increased expression of mesenchymal markers. Withdrawal of TGF-β1 reversed the process of EMT with elevated expression of epithelial markers and reduced expression of mesenchymal markers. TGF-β1 treatment elevated the migratory potential of HCC cells which was reversed following reversal assay. Notably, during TGF-β1-induced EMT, there was upregulation of immune checkpoint molecules PD-L1 and B7-H3. However, the reversal of EMT decreased the expression of PD-L1 and B7-H3. In addition, TGF-β1 driven EMT was reversed following knockdown of B7-H3 in both HCC cells further validating the interplay between TGF-β1-mediated EMT and immune checkpoint expression in HCC. Furthermore, the coordinate expression of TGF-β1 with PD-L1 (p=0.01487) and B7-H3 (p=0.009687) was correlated with poor overall survival in 422 HCC patients. Our study has demonstrated a close association between TGF-β1-mediated EMT and regulation of immune checkpoints in HCC.
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Affiliation(s)
- Ritu Shrestha
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Kim R Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Darrell H G Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia
| | - Aparna Jayachandran
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland, Australia.,Fiona Elsey Cancer Research Institute, Ballarat, Victoria, Australia
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Cheng R, Wang B, Cai XR, Chen ZS, Du Q, Zhou LY, Ye JM, Chen YL. CD276 Promotes Vasculogenic Mimicry Formation in Hepatocellular Carcinoma via the PI3K/AKT/MMPs Pathway. Onco Targets Ther 2020; 13:11485-11498. [PMID: 33204103 PMCID: PMC7667184 DOI: 10.2147/ott.s271891] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose CD276 protein expression and vasculogenic mimicry (VM) formation are associated with the poor prognosis of hepatocellular carcinoma (HCC) patients. Although both the effects of CD276 and VM formation involve the activation of matrix metalloproteinases, and their relationship has not yet been explored. The following study investigated the effect of CD276 expression on VM formation and the potential mechanisms. Materials and Methods CD276 expression and VM were examined in commercial tissue microarrays by immunohistochemistry and CD31/PAS double staining. Tumor cell proliferation, invasion, migration and, tube formation were detected in vitro after transfecting HCC cell lines with an shRNA lentiviral vector against CD276. The expression of MMP14, MMP2, VE-cadherin, E-cadherin, and vimentin and MMPs activation was detected by Western blot, immunofluorescence and gelatin zymography assay. In addition, an orthotopic xenograft model of HCC cells was established in vivo, after which VM was detected, along with its marker molecules. Results CD276 expression was associated with VM and poor prognosis in HCC patients. RNA interference of CD276 reduced tumor cell proliferation, invasion, migration, and VM formation in vitro and in vivo. Furthermore, CD276 knockdown up-regulated the expression of E-cadherin but inhibited the phosphorylation of AKT, the expression of MMP14, MMP2, VE-cadherin, vimentin and the activation of MMP2 and MMP9 in HCC cell lines. Conclusion CD276 may promote VM formation by activating the PI3K/AKT/MMPs pathway and inducing the EMT process in HCC. CD276 may serve as a promising candidate for the anti-VM treatment of HCC.
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Affiliation(s)
- Rui Cheng
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Bi Wang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Xin-Ran Cai
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Zhi-Shan Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Qiang Du
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Liang-Yi Zhou
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Jing-Min Ye
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Yan-Ling Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China.,Fujian Medical University Cancer Center, Fuzhou, Fujian 350001, People's Republic of China
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Abstract
PURPOSE OF REVIEW Immunotherapy has shown an unprecedented response in treatment of tumors. However, challenges such as lack of cytotoxic lymphocytes to mount an immune response or development of resistance to therapy can limit efficacy. Here, we discuss alternative checkpoints that can be targeted to improve cytotoxic lymphocyte function while harnessing other components of the immune system. RECENT FINDINGS Blockade of alternative checkpoints has improved anti-tumor immunity in mouse models and is being tested clinically with encouraging findings. In addition to modulating T cell function directly, alternative checkpoints can also regulate activity of myeloid cells and regulatory T cells to affect anti-tumor response. Combination of immune checkpoint inhibitors can improve treatment of tumors by activating multiple arms of the immune system.
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Affiliation(s)
- Ayush Pant
- Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, and Institute of NanoBiotechnology, Brain Tumor Immunotherapy Program, Metastatic Brain Tumor Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA
| | - Ravi Medikonda
- Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, and Institute of NanoBiotechnology, Brain Tumor Immunotherapy Program, Metastatic Brain Tumor Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA
| | - Michael Lim
- Department of Neurosurgery, Neurosurgery Oncology, Radiation Oncology, Otolaryngology, and Institute of NanoBiotechnology, Brain Tumor Immunotherapy Program, Metastatic Brain Tumor Center, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD, 21287, USA.
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B7-H3 expression in upper tract urothelial carcinoma associates with adverse clinicopathological features and poor survival. Pathol Res Pract 2020; 216:153219. [PMID: 33049447 DOI: 10.1016/j.prp.2020.153219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/10/2020] [Accepted: 09/14/2020] [Indexed: 12/17/2022]
Abstract
B7-H3, a member of the B7 superfamily, is an immune checkpoint molecule. An association between B7-H3 expression and poor survival has been reported in many types of cancer. However, its prognostic value in patients with upper tract urothelial carcinoma (UTUC) has not yet been reported. The aim of this study was to examine the clinical significance of tumor B7-H3 expression in UTUC. B7-H3 positivity was observed in 36 of 271 cases (13 %) by immunohistochemistry and was significantly associated with several adverse clinicopathological features such as tumor grade, tumor stage, and lymph node metastasis. In addition, B7-H3 positivity was significantly associated with shorter metastasis-free survival and cancer-specific survival. We also found that B7-H3/programmed cell death ligand-1 (PD-L1) co-positivity was significantly associated with worse prognosis. These results suggest the utility of B7-H3 positivity and B7-H3/PD-L1 co-positivity as novel prognostic biomarkers in UTUC, and the potential usefulness of B7-H3 targeted therapy for patients with UTUC, the effect of which may be enhanced by combination with programmed cell death-1 /PD-L1 blockade.
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Zhang T, Jin Y, Jiang X, Li L, Qi X, Mao Y, Hua D. Clinical and Prognostic Relevance of B7-H3 and Indicators of Glucose Metabolism in Colorectal Cancer. Front Oncol 2020; 10:546110. [PMID: 33042836 PMCID: PMC7523031 DOI: 10.3389/fonc.2020.546110] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
Objective This study aimed to investigate the clinical and prognostic relevance of B7-H3 expression and indicators of glucose metabolism in patients with colorectal cancer (CRC). Methods Using immunohistochemistry, the expression of B7-H3 was detected in a total of 213 formalin-fixed paraffin-embedded CRC tissue specimens. Furthermore, levels of fasting blood glucose (FBG), lactic dehydrogenase (LDH), and fructosamine (FMN) as indicators of glucose metabolism were analyzed in CRC patients and stratified into high or low expression sub-groups based on Youden Index. The relationship between B7-H3, FBG, LDH, FMN expression, and clinicopathological characteristics were also evaluated to establish their prognostic significance in patients with CRC. Results B7-H3 was highly expressed in CRC tissue. The positive rates of B7-H3 expression was 63.8% (136/213). We found a linear correlation between B7-H3 and FBG in depth of tumor invasion (T3/4) (p = 0.037, r = 0.259), lymph node metastasis (N0) (p = 0.004, r = 0.259), and TNM stage (I/II) (p = 0.009, r = 0.242). High expression of FBG, LDH, FMN [hazard ratio (HR) = 1.916, 95% CI: 1.223–3.00, p = 0.005; HR = 1.801, 95% CI: 1.153–2.813, p = 0.010; HR = 2.154, 95% CI: 1.336–3.472, p = 0.002], respectively, was identified as a significant independent predictor of poor overall survival (OS). Although B7-H3 expression did not affect OS, CRC patients expressing both high B7-H3 and high FMN contributed to a significant decrease in OS (HR = 1.881, 95%CI: 1.059–3.339, p = 0.031). Moreover, with low expression of B7-H3, high expression of FBG, LDH and FMN were also recognized as predictors of inferior OS (HR = 3.393, 95% CI: 1.493-7.709, p = 0.004; HR = 7.107, 95% CI: 2.785–18.138, p = 0.000; HR = 2.800, 95% CI: 1.184–6.625, p = 0.019). Conclusion B7-H3 combined with FBG, LDH, or FMN, could reflect the clinical outcomes of patients with CRC.
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Affiliation(s)
- Ting Zhang
- Institue of Cancer, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yufen Jin
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xin Jiang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Longhai Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaowei Qi
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.,Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yong Mao
- Wuxi School of Medicine, Jiangnan University, Wuxi, China.,Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Dong Hua
- Institue of Cancer, Affiliated Hospital of Jiangnan University, Wuxi, China.,Wuxi School of Medicine, Jiangnan University, Wuxi, China.,Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
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Flem-Karlsen K, Fodstad Ø, Nunes-Xavier CE. B7-H3 Immune Checkpoint Protein in Human Cancer. Curr Med Chem 2020; 27:4062-4086. [PMID: 31099317 DOI: 10.2174/0929867326666190517115515] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 04/29/2019] [Accepted: 05/04/2019] [Indexed: 02/07/2023]
Abstract
B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.
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Affiliation(s)
- Karine Flem-Karlsen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Caroline E Nunes-Xavier
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
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Wang C, Feng H, Cheng X, Liu K, Cai D, Zhao R. Potential Therapeutic Targets of B7 Family in Colorectal Cancer. Front Immunol 2020; 11:681. [PMID: 32477326 PMCID: PMC7232583 DOI: 10.3389/fimmu.2020.00681] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway blockade has impressively benefited cancer patients with a wide spectrum of tumors. However, its efficacy in colorectal cancer (CRC) is modest, and only a small subset of patients benefits from approved checkpoint inhibitors. Newer checkpoints that target additional immunomodulatory pathways are becoming necessary to activate durable antitumor immune responses in patients with CRC. In this review, we evaluated the mRNA expression of all 10 reported B7 family members in human CRC by retrieving and analyzing the TCGA database and reviewed the current understanding of the top three B7 family checkpoint molecules (B7-H3, VISTA, and HHLA2) with the highest mRNA expression, introducing them as putative therapeutic targets in CRC.
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Affiliation(s)
- Changgang Wang
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoran Feng
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Cheng
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Liu
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongli Cai
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ren Zhao
- Department of General Surgery, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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48
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 01/27/2025] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
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MESH Headings
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cancer Vaccines/administration & dosage
- Combined Modality Therapy/methods
- Dendritic Cells/immunology
- Drug Resistance, Neoplasm/immunology
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Neoplasms/therapy
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Innate/drug effects
- Immunity, Innate/immunology
- Immunotherapy/methods
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Tumor Escape/drug effects
- Tumor Escape/immunology
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania.
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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49
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
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MESH Headings
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Cancer Vaccines/administration & dosage
- Combined Modality Therapy/methods
- Dendritic Cells/immunology
- Drug Resistance, Neoplasm/immunology
- Gastrointestinal Neoplasms/immunology
- Gastrointestinal Neoplasms/pathology
- Gastrointestinal Neoplasms/therapy
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Innate/drug effects
- Immunity, Innate/immunology
- Immunotherapy/methods
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/prevention & control
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Tumor Escape/drug effects
- Tumor Escape/immunology
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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50
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Shrestha R, Bridle KR, Crawford DHG, Jayachandran A. TNF‑α‑mediated epithelial‑to‑mesenchymal transition regulates expression of immune checkpoint molecules in hepatocellular carcinoma. Mol Med Rep 2020; 21:1849-1860. [PMID: 32319631 PMCID: PMC7057769 DOI: 10.3892/mmr.2020.10991] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 01/31/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths globally. Epithelial-to-mesenchymal transition (EMT) is a cellular process that confers HCC tumor cells with the ability to evade the immune system. Immune escape in most tumors, including HCC, is controlled by immune checkpoint molecules. The aim of the present study was to investigate the association between EMT and immune checkpoint in HCC, and identify novel therapeutic targets for HCC. An in vitro model of reversible EMT was utilized based on cytokine tumor necrosis factor (TNF)-α treatment of HCC cell lines Hep3B and PLC/PRF/5. Hep3B and PLC/PRF/5 cells were treated with TNF-α, and the EMT status and the expression of immune checkpoint molecules was assessed by reverse transcription-quantitative PCR, western blotting and immunofluorescence. To confirm an association between EMT and immune modulators, cells were exposed to culture medium with TNF-α for 3 days to induce EMT, following which a reversal assay was performed. The expression of immune modulators and mesenchymal-to-epithelial transition (MET) status was investigated upon reversal of EMT. Furthermore, SurvExpress, a web-based platform was utilized to analyze survival and recurrence in a dataset of patients with HCC. TNF-α treatment for 3 days induced EMT in Hep3B and PLC/PRF/5 cells, as demonstrated by the downregulation of epithelial markers along with upregulation in mesenchymal markers. An EMT reversal assay was able to induce MET by increasing epithelial markers and decreasing mesenchymal markers. TNF-α-induced EMT led to the upregulation of immune modulators, including programmed death receptor ligand (PD-L)1, PD-L2, CD73 and B7-H3. In contrast, reversal of EMT suppressed the expression of PD-L1, PD-L2, CD73 and B7-H3. In addition, high expression of TNF-α and PD-L1 in 422 patients with HCC was associated with poor overall survival. The coordinate expression of TNF-α with PD-L2 in this patient cohort was associated with increased HCC recurrence. In conclusion, the present study demonstrated a close association between immune modulator expression and EMT induction/reversal driven by TNF-α.
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Affiliation(s)
- Ritu Shrestha
- University of Queensland, Faculty of Medicine, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Kim R Bridle
- University of Queensland, Faculty of Medicine, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Darrell H G Crawford
- University of Queensland, Faculty of Medicine, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Aparna Jayachandran
- University of Queensland, Faculty of Medicine, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
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