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Bai J, Xiao R, Jiang D, Luo X, Tang Y, Cui M, You L, Zhao Y. Sialic Acids: Sweet modulators fueling cancer cells and domesticating the tumor microenvironment. Cancer Lett 2025; 626:217773. [PMID: 40339953 DOI: 10.1016/j.canlet.2025.217773] [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: 03/10/2025] [Revised: 04/23/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Tumor microenvironment (TME) can shift towards either immune activation or immunosuppression, influenced by various factors. Recent studies have underscored the pivotal role of sialic acids, a group of monosaccharides with a 9-carbon backbone, in modulating the TME. Aberrant expression or abnormal addition of sialic acids to the surface of cancer cells and within the tumor stroma has been identified as a key contributor to tumor progression. Abnormal sialylation on cancer cell surfaces can inhibit apoptosis, enhance cell proliferation, and facilitate metastasis. Notably, recent findings suggest that dysregulated sialic acid expression in the TME actively contributes to shaping an immunosuppressive niche by reducing the population of anti-tumor immune cells and impairing immune cell function. The mechanisms by which sialic acids foster immune escape and shape the immunosuppressive TME have been partially unraveled, particularly through interactions with sialic acid receptors on immune cells. Importantly, several sialic acid-targeted therapies are currently advancing into clinical trials, offering promising prospects for clinical translation. This dysregulated sialylation represents a significant opportunity for molecular diagnostics and therapeutic interventions in oncology. Targeting aberrant sialylation or disrupting the interaction between sialic acids and their receptors offers potential strategies to reprogram the TME towards an anti-tumor phenotype, thereby facilitating the advancement of innovative cancer therapies.
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Affiliation(s)
- Jialu Bai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ruiling Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Decheng Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xiyuan Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yuemeng Tang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ming Cui
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Freitas R, Peixoto A, Santos LL, Ferreira JA. Glycan-based therapeutic approaches for bladder cancer: Overcoming clinical barriers. Biochim Biophys Acta Rev Cancer 2025; 1880:189327. [PMID: 40274080 DOI: 10.1016/j.bbcan.2025.189327] [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: 01/03/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025]
Abstract
Bladder cancer (BLCA) remains a significant global health concern, being characterized by high incidence, recurrence, and mortality rates. Disease heterogeneity and rapid progression pose major challenges for effective management and identification of actionable biomarkers. Conventional therapies often fail to successfully achieve disease control, urging the development of novel, personalized approaches. In recent years, anti-tumour immunotherapy approaches in both pre-clinical and clinical settings have boomed. However, the efficacy of these strategies has been limited by the low mutational burden in some tumours, which hinders neoantigen presentation and the identification of BLCA-specific signatures. Cancer-associated aberrant glycosylation presents a unique opportunity for identifying BLCA-specific glycosignatures and developing innovative targeted therapeutics. This review provides a comprehensive overview of the clinical challenges in BLCA management and emerging novel therapies. Furthermore, it highlights the potential of glycosylation alterations as a unique opportunity for developing glycan-based therapies, potentially revolutionizing BLCA treatment strategies.
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Affiliation(s)
- Rui Freitas
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; i3S - Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; i3S - Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; ICBAS - School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; i3S - Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; INEB - Institute for Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal; Health School of University Fernando Pessoa, 4249-004 Porto, Portugal; Department of Surgical Oncology, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal; CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC Raquel Seruca), 4200-072 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal..
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Abrantes R, Lopes J, Lopes D, Gomes J, Melo SA, Reis CA. Sialyl-Tn glycan epitope as a target for pancreatic cancer therapies. Front Oncol 2024; 14:1466255. [PMID: 39346741 PMCID: PMC11427427 DOI: 10.3389/fonc.2024.1466255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/19/2024] [Indexed: 10/01/2024] Open
Abstract
Pancreatic cancer (PC) is the sixth leading cause of cancer-related deaths worldwide, primarily due to late-stage diagnosis and limited treatment options. While novel biomarkers and immunotherapies are promising, further research into specific molecular targets is needed. Glycans, which are carbohydrate structures mainly found on cell surfaces, play crucial roles in health and disease. The Thomsen-Friedenreich-related carbohydrate antigen Sialyl-Tn (STn), a truncated O-glycan structure, is selectively expressed in epithelial tumors, including PC. In this study, we performed a comprehensive analysis of STn expression patterns in normal, premalignant, and malignant pancreatic lesions. Additionally, we analyzed the association between STn expression and various clinicopathological features. STn expression was statistically associated with pathological diagnosis; it was absent in normal pancreatic tissue but prevalent in pancreatic carcinoma lesions, including pancreatic ductal adenocarcinoma (PDAC), pancreatic acinar cell carcinoma, and pancreatic adenosquamous carcinoma. Moreover, we found a significant association between STn expression and tumor stage, with higher STn levels observed in stage II tumors compared to stage I. However, STn expression did not correlate with patient survival or outcomes. Furthermore, STn expression was assessed in PDAC patient-derived xenograft (PDX) models, revealing consistent STn levels throughout engraftment and tumor growth cycles. This finding supports the PDX model as a valuable tool for testing new anti-STn therapeutic strategies for PC in clinical setting.
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Affiliation(s)
- Rafaela Abrantes
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Joanne Lopes
- Department of Pathology, Unidade Local de Saúde (ULS) de São João, Porto, Portugal
| | - Daniel Lopes
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
| | - Joana Gomes
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Sónia A. Melo
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Porto Comprehensive Cancer Center (P.CCC), Porto, Portugal
| | - Celso A. Reis
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Porto Comprehensive Cancer Center (P.CCC), Porto, Portugal
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Niveau C, Sosa Cuevas E, Saas P, Aspord C. Glycans in melanoma: Drivers of tumour progression but sweet targets to exploit for immunotherapy. Immunology 2024; 173:33-52. [PMID: 38742251 DOI: 10.1111/imm.13801] [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: 02/25/2024] [Accepted: 05/03/2024] [Indexed: 05/16/2024] Open
Abstract
Aberrant glycosylation recently emerged as an unmissable hallmark of cancer progression in many cancers. In melanoma, there is growing evidence that the tumour 'glycocode' plays a major role in promoting cell proliferation, invasion, migration, but also dictates the nature of the immune infiltrate, which strongly affects immune cell function, and clinical outcome. Aberrant glycosylation patterns dismantle anti-tumour defence through interactions with lectins on immune cells, which are crucial to shape anti-tumour immunity but also to trigger immune evasion. The glycan/lectin axis represents a new immune subversion pathway that is exploited by melanoma to hijack immune cells and escape from immune control. In this review, we describe the glycosylation features of melanoma tumour cells, and further gather findings related to the role of glycosylation in melanoma tumour progression, deciphering in detail its impact on immunity. We also depict glycan-based strategies aiming at restoring a functional anti-tumour response in melanoma patients. Glycans/lectins emerge as key immune checkpoints with promising translational properties. Exploitation of these pathways could reshape potent anti-tumour immunity while impeding immunosuppressive circuits triggered by aberrant tumour glycosylation patterns, holding great promise for cancer therapy.
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Affiliation(s)
- Camille Niveau
- Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France
| | - Eleonora Sosa Cuevas
- Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France
| | - Philippe Saas
- Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France
| | - Caroline Aspord
- Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France
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Sun Y, Gan Z, Wang X, Liu J, Zhong W, Zhang Z, Zuo J, Zhong H, Huang X, Yan Z, Cao Q. Integrative metagenomic, transcriptomic, and proteomic analysis reveal the microbiota-host interplay in early-stage lung adenocarcinoma among non-smokers. J Transl Med 2024; 22:652. [PMID: 38997719 PMCID: PMC11245786 DOI: 10.1186/s12967-024-05485-0] [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: 12/15/2023] [Accepted: 07/03/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND The incidence of early-stage lung adenocarcinoma (ES-LUAD) is steadily increasing among non-smokers. Previous research has identified dysbiosis in the gut microbiota of patients with lung cancer. However, the local microbial profile of non-smokers with ES-LUAD remains largely unknown. In this study, we systematically characterized the local microbial community and its associated features to enable early intervention. METHODS A prospective collection of ES-LUAD samples (46 cases) and their corresponding normal tissues adjacent to the tumor (41 cases), along with normal lung tissue samples adjacent to pulmonary bullae in patients with spontaneous pneumothorax (42 cases), were subjected to ultra-deep metagenomic sequencing, host transcriptomic sequencing, and proteomic sequencing. The obtained omics data were subjected to both individual and integrated analysis using Spearman correlation coefficients. RESULTS We concurrently detected the presence of bacteria, fungi, and viruses in the lung tissues. The microbial profile of ES-LUAD exhibited similarities to NAT but demonstrated significant differences from the healthy controls (HCs), characterized by an overall reduction in species diversity. Patients with ES-LUAD exhibited local microbial dysbiosis, suggesting the potential pathogenicity of certain microbial species. Through multi-omics correlations, intricate local crosstalk between the host and local microbial communities was observed. Additionally, we identified a significant positive correlation (rho > 0.6) between Methyloversatilis discipulorum and GOLM1 at both the transcriptional and protein levels using multi-omics data. This correlated axis may be associated with prognosis. Finally, a diagnostic model composed of six bacterial markers successfully achieved precise differentiation between patients with ES-LUAD and HCs. CONCLUSIONS Our study depicts the microbial spectrum in patients with ES-LUAD and provides evidence of alterations in lung microbiota and their interplay with the host, enhancing comprehension of the pathogenic mechanisms that underlie ES-LUAD. The specific model incorporating lung microbiota can serve as a potential diagnostic tool for distinguishing between ES-LUAD and HCs.
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Affiliation(s)
- Yaohui Sun
- Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Zhiming Gan
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Xiaojin Wang
- Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Jian Liu
- Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Wei Zhong
- Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Zhiyan Zhang
- Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Jiebin Zuo
- Cardiovascular Disease Center, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Hang Zhong
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Xiuting Huang
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China
| | - Zhixiang Yan
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China.
| | - Qingdong Cao
- Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China.
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Silva Z, Soares CO, Barbosa M, Palma AS, Marcelo F, Videira PA. The role of sialoglycans in modulating dendritic cell function and tumour immunity. Semin Immunol 2024; 74-75:101900. [PMID: 39461124 DOI: 10.1016/j.smim.2024.101900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/15/2024] [Accepted: 10/15/2024] [Indexed: 10/29/2024]
Abstract
Dendritic cells (DCs) are crucial for initiating immune responses against tumours by presenting antigens to T cells. Glycosylation, particularly sialylation, plays a significant role in regulating cell functions, by modulating protein folding and signalling. This review aimed to provide a comprehensive overview of how sialic acids influence key aspects of DC biology, including maturation, migration, antigen presentation, and T cell interactions. Sialic acids influence DC endocytosis, affecting their ability to uptake and present antigens, while guiding their migration to lymph nodes and inflamed tissues. Removing sialic acids enhances DC-mediated antigen presentation to T cells, potentially boosting immune responses. Additionally, sialylated glycans on DCs modulate immune checkpoints, which can impact tumour immunity. Hypersialylation of tumour mucins further promotes immune evasion by interacting with DCs. Understanding the interplay between sialylation and DC functions offers promising avenues for enhancing cancer immunotherapy.
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Affiliation(s)
- Zélia Silva
- Institute for Health and Bioeconomy (i4HB), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; CDG & Allies - Professionals and Patient Associations International Network (CDG & Allies - PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal
| | - Cátia O Soares
- Institute for Health and Bioeconomy (i4HB), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal
| | - Mariana Barbosa
- Institute for Health and Bioeconomy (i4HB), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; CDG & Allies - Professionals and Patient Associations International Network (CDG & Allies - PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal
| | - Angelina S Palma
- Institute for Health and Bioeconomy (i4HB), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal
| | - Filipa Marcelo
- Institute for Health and Bioeconomy (i4HB), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal
| | - Paula A Videira
- Institute for Health and Bioeconomy (i4HB), NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal; CDG & Allies - Professionals and Patient Associations International Network (CDG & Allies - PPAIN), Department of Life Sciences, NOVA School of Science and Technology, Universidade NOVA de Lisboa, Caparica 2829-516, Portugal.
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Ren X, Lin S, Guan F, Kang H. Glycosylation Targeting: A Paradigm Shift in Cancer Immunotherapy. Int J Biol Sci 2024; 20:2607-2621. [PMID: 38725856 PMCID: PMC11077373 DOI: 10.7150/ijbs.93806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
Immunotherapy has shown great potential in cancer treatment. However, even with the intervention of techniques such as immune checkpoint inhibitor therapy, tumors can still achieve immune escape, leading to a low response rate. Abnormal glycosylation is a widely recognized hallmark of cancer. The development of a complex "glyco-code" on the surface of tumor cells can potentially influence the immune system's ability to monitor tumors and can impact the anti-tumor immune response. Therefore, abnormal glycosylation has emerged as a promising target for immunotherapy. Many recent studies have shown that targeted glycosylation can reshape the tumor microenvironment (TME) and promote the immune response, thereby improving the response to immunotherapy. This review summarizes how glycosylation affects anti-tumor immune function in the TME and synthesizes the latest research progress on targeted glycosylation in immunotherapy. It is hoped that by elucidating the basic laws and biological connotations of glycosylation, this review will enable researcher to thoroughly analyze the mechanism of its influence on the immune metabolic regulation network, which will provide a theoretical tool for promoting the clinical application of glycosylation codes.
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Affiliation(s)
- Xueting Ren
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shuai Lin
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Huafeng Kang
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Al-Alem L, Prendergast JM, Clark J, Zarrella B, Zarrella DT, Hill SJ, Growdon WB, Pooladanda V, Spriggs DR, Cramer D, Elias KM, Nazer RI, Skates SJ, Behrens J, Dransfield DT, Rueda BR. Sialyl-Tn serves as a potential therapeutic target for ovarian cancer. J Ovarian Res 2024; 17:71. [PMID: 38566237 PMCID: PMC10985924 DOI: 10.1186/s13048-024-01397-1] [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: 08/24/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer. METHODS We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples. RESULTS Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis. CONCLUSIONS Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.
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Affiliation(s)
- Linah Al-Alem
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA
| | | | - Justin Clark
- Siamab Therapeutics, Inc, Newton, MA, 02458, USA
| | - Bianca Zarrella
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Dominique T Zarrella
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Sarah J Hill
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Whitfield B Growdon
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Venkatesh Pooladanda
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - David R Spriggs
- Division of Hematology-Oncology, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Daniel Cramer
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Kevin M Elias
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | | | - Steven J Skates
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Jeff Behrens
- Siamab Therapeutics, Inc, Newton, MA, 02458, USA
| | | | - Bo R Rueda
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, 02115, USA.
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA.
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9
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Luo Y, Cao H, Lei C, Liu J. ST6GALNAC1 promotes the invasion and migration of breast cancer cells via the EMT pathway. Genes Genomics 2023; 45:1367-1376. [PMID: 37747641 DOI: 10.1007/s13258-023-01445-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 08/28/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND A specific sialyl-transferases called ST6GALNAC1 has been proven to up-regulate abnormal O-glycosylation, which is strongly associated with tumorigenesis and cancer progression. However, the precise pathological outcome of ST6GALNAC1 expression in breast cancer cells remains unknown. Therefore, our study aims to investigate the functional role of ST6GALNAC1 and its impact on the epithelial-mesenchymal transition (EMT) pathway in breast cancer cells. METHODS Plasmids with siRNA were used to construct ST6GALNAC1 knockoff (si-ST6GALNAC1) MDA-MB-231 and MDA-MB-453 cells, while lentiviruses were used to construct ST6GALNAC1 over-expression (oe-ST6GALNAC1) MCF-7 and BT474 cells. Transfer efficiency was verified by Western Blot. Then we selected transfected cells and assessed the changes in cell proliferation, invasion, migration, and EMT markers. RESULTS The expression of ST6GALNAC1 significantly enhanced cell migration and invasion, which was confirmed by Wound Scratch Assay and Transwell Assay. Particularly, ST6GALNAC1 expression directly induced the EMT signaling pathway. E-cadherin was markedly decreased in oe-ST6GALNAC1 cells, accompanied by an up-regulation of mesenchymal markers including N-cadherin, snail, and ZEB1. However, no significant correlation was found between ST6GALNAC1 expression and cell proliferation. All of the outcomes were reversely validated in si-ST6GALNAC1 cells. CONCLUSIONS The expression of ST6GALNAC1 promotes cell migration and invasion probably by triggering the molecular process of the EMT pathway in breast cancer cells, which may provide new clues for designing novel molecular targeted drugs in breast cancer treatment.
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Affiliation(s)
- Yunzhao Luo
- Department of Breast Surgery, Beijing Chaoyang Hospital of Capital Medical University, No. 8 Workers' Stadium South Road, Beijing, 100020, China
| | - Heng Cao
- Department of Breast Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Chuqi Lei
- Department of Breast Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Jun Liu
- Department of Breast Surgery, Beijing Chaoyang Hospital of Capital Medical University, No. 8 Workers' Stadium South Road, Beijing, 100020, China.
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10
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Lodewijk I, Dueñas M, Paramio JM, Rubio C. CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies. Front Immunol 2023; 14:1272681. [PMID: 37854601 PMCID: PMC10579806 DOI: 10.3389/fimmu.2023.1272681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/14/2023] [Indexed: 10/20/2023] Open
Abstract
Targeted therapies are the state of the art in oncology today, and every year new Tumor-associated antigens (TAAs) are developed for preclinical research and clinical trials, but few of them really change the therapeutic scenario. Difficulties, either to find antigens that are solely expressed in tumors or the generation of good binders to these antigens, represent a major bottleneck. Specialized cellular mechanisms, such as differential splicing and glycosylation processes, are a good source of neo-antigen expression. Changes in these processes generate surface proteins that, instead of showing decreased or increased antigen expression driven by enhanced mRNA processing, are aberrant in nature and therefore more specific targets to elicit a precise anti-tumor therapy. Here, we present promising TAAs demonstrated to be potential targets for cancer monitoring, targeted therapy and the generation of new immunotherapy tools, such as recombinant antibodies and chimeric antigen receptor (CAR) T cell (CAR-T) or Chimeric Antigen Receptor-Engineered Natural Killer (CAR-NK) for specific tumor killing, in a wide variety of tumor types. Specifically, this review is a detailed update on TAAs CD44v6, STn and O-GD2, describing their origin as well as their current and potential use as disease biomarker and therapeutic target in a diversity of tumor types.
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Affiliation(s)
- Iris Lodewijk
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Marta Dueñas
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Jesus M. Paramio
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Carolina Rubio
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
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11
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Matsumoto Y, Ju T. Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors. Cancers (Basel) 2023; 15:3536. [PMID: 37509200 PMCID: PMC10377354 DOI: 10.3390/cancers15143536] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/01/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023] Open
Abstract
Glycosylation occurs at all major types of biomolecules, including proteins, lipids, and RNAs to form glycoproteins, glycolipids, and glycoRNAs in mammalian cells, respectively. The carbohydrate moiety, known as glycans on glycoproteins and glycolipids, is diverse in their compositions and structures. Normal cells have their unique array of glycans or glycome which play pivotal roles in many biological processes. The glycan structures in cancer cells, however, are often altered, some having unique structures which are termed as tumor-associated carbohydrate antigens (TACAs). TACAs as tumor biomarkers are glycan epitopes themselves, or glycoconjugates. Some of those TACAs serve as tumor glyco-biomarkers in clinical practice, while others are the immune therapeutic targets for treatment of cancers. A monoclonal antibody (mAb) to GD2, an intermediate of sialic-acid containing glycosphingolipids, is an example of FDA-approved immune therapy for neuroblastoma indication in young adults and many others. Strategies for targeting the aberrant glycans are currently under development, and some have proceeded to clinical trials. In this review, we summarize the currently established and most promising aberrant glycosylation as therapeutic targets for solid tumors.
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Affiliation(s)
- Yasuyuki Matsumoto
- Office of Biotechnology Products, Center for Drug Evaluation and Research, The U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Tongzhong Ju
- Office of Biotechnology Products, Center for Drug Evaluation and Research, The U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
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12
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Wilczak M, Surman M, Przybyło M. Altered Glycosylation in Progression and Management of Bladder Cancer. Molecules 2023; 28:molecules28083436. [PMID: 37110670 PMCID: PMC10146225 DOI: 10.3390/molecules28083436] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/05/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Bladder cancer (BC) is the 10th most common malignancy worldwide, with an estimated 573,000 new cases and 213,000 deaths in 2020. Available therapeutic approaches are still unable to reduce the incidence of BC metastasis and the high mortality rates of BC patients. Therefore, there is a need to deepen our understanding of the molecular mechanisms underlying BC progression to develop new diagnostic and therapeutic tools. One such mechanism is protein glycosylation. Numerous studies reported changes in glycan biosynthesis during neoplastic transformation, resulting in the appearance of the so-called tumor-associated carbohydrate antigens (TACAs) on the cell surface. TACAs affect a wide range of key biological processes, including tumor cell survival and proliferation, invasion and metastasis, induction of chronic inflammation, angiogenesis, immune evasion, and insensitivity to apoptosis. The purpose of this review is to summarize the current information on how altered glycosylation of bladder cancer cells promotes disease progression and to present the potential use of glycans for diagnostic and therapeutic purposes.
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Affiliation(s)
- Magdalena Wilczak
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9 Street, 30-387 Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Prof. S. Łojasiewicza 11 Street, 30-348 Krakow, Poland
| | - Magdalena Surman
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9 Street, 30-387 Krakow, Poland
| | - Małgorzata Przybyło
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9 Street, 30-387 Krakow, Poland
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13
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Freitas R, Peixoto A, Ferreira E, Miranda A, Santos LL, Ferreira JA. Immunomodulatory glycomedicine: Introducing next generation cancer glycovaccines. Biotechnol Adv 2023; 65:108144. [PMID: 37028466 DOI: 10.1016/j.biotechadv.2023.108144] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 03/17/2023] [Accepted: 03/30/2023] [Indexed: 04/09/2023]
Abstract
Cancer remains a leading cause of death worldwide due to the lack of safer and more effective therapies. Cancer vaccines developed from neoantigens are an emerging strategy to promote protective and therapeutic anti-cancer immune responses. Advances in glycomics and glycoproteomics have unveiled several cancer-specific glycosignatures, holding tremendous potential to foster effective cancer glycovaccines. However, the immunosuppressive nature of tumours poses a major obstacle to vaccine-based immunotherapy. Chemical modification of tumour associated glycans, conjugation with immunogenic carriers and administration in combination with potent immune adjuvants constitute emerging strategies to address this bottleneck. Moreover, novel vaccine vehicles have been optimized to enhance immune responses against otherwise poorly immunogenic cancer epitopes. Nanovehicles have shown increased affinity for antigen presenting cells (APCs) in lymph nodes and tumours, while reducing treatment toxicity. Designs exploiting glycans recognized by APCs have further enhanced the delivery of antigenic payloads, improving glycovaccine's capacity to elicit innate and acquired immune responses. These solutions show potential to reduce tumour burden, while generating immunological memory. Building on this rationale, we provide a comprehensive overview on emerging cancer glycovaccines, emphasizing the potential of nanotechnology in this context. A roadmap towards clinical implementation is also delivered foreseeing advances in glycan-based immunomodulatory cancer medicine.
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Affiliation(s)
- Rui Freitas
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal; Abel Salazar Biomedical Sciences Institute - University of Porto (ICBAS), 4050-313 Porto, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal
| | - Eduardo Ferreira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal
| | - Andreia Miranda
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Abel Salazar Biomedical Sciences Institute - University of Porto (ICBAS), 4050-313 Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal; Abel Salazar Biomedical Sciences Institute - University of Porto (ICBAS), 4050-313 Porto, Portugal; Health School of University Fernando Pessoa, 4249-004 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal; Department of Surgical Oncology, Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal; GlycoMatters Biotech, 4500-162 Espinho, Portugal.
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14
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Matsumoto Y, Jia N, Heimburg-Molinaro J, Cummings RD. Targeting Tn-positive tumors with an afucosylated recombinant anti-Tn IgG. Sci Rep 2023; 13:5027. [PMID: 36977722 PMCID: PMC10050417 DOI: 10.1038/s41598-023-31195-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
The aberrant expression of the Tn antigen (CD175) on surface glycoproteins of human carcinomas is associated with tumorigenesis, metastasis, and poor survival. To target this antigen, we developed Remab6, a recombinant, human chimeric anti-Tn-specific monoclonal IgG. However, this antibody lacks antibody-dependent cell cytotoxicity (ADCC) effector activity, due to core fucosylation of its N-glycans. Here we describe the generation of an afucosylated Remab6 (Remab6-AF) in HEK293 cells in which the FX gene is deleted (FXKO). These cells cannot synthesize GDP-fucose through the de novo pathway, and lack fucosylated glycans, although they can incorporate extracellularly-supplied fucose through their intact salvage pathway. Remab6-AF has strong ADCC activity against Tn+ colorectal and breast cancer cell lines in vitro, and is effective in reducing tumor size in an in vivo xenotransplant mouse model. Thus, Remab6-AF should be considered as a potential therapeutic anti-tumor antibody against Tn+ tumors.
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Affiliation(s)
- Yasuyuki Matsumoto
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Nan Jia
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Jamie Heimburg-Molinaro
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA.
- Department of Surgery, Surgical Sciences, Beth Israel Deaconess Medical Center, CLS 11087, 3 Blackfan Circle, Boston, MA, 02115, USA.
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15
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Rajesh C, Radhakrishnan P. The (Sialyl) Tn antigen: Contributions to immunosuppression in gastrointestinal cancers. Front Oncol 2023; 12:1093496. [PMID: 36686742 PMCID: PMC9852904 DOI: 10.3389/fonc.2022.1093496] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Cellular signaling pathways are intricately regulated to maintain homeostasis. During cancer progression, these mechanisms are manipulated to become harmful. O-glycosylation, a crucial post-translational modification, is one such pathway that can lead to multiple isoforms of glycoproteins. The Tn (GalNAc-O-Ser/Thr) and Sialyl Tn (STn; Neu5Ac-GalNAc-O-Ser/Thr) antigens resulting from the incomplete synthesis of fully branched O-glycan chains on proteins contribute to disease progression in the pancreas and other gastrointestinal cancers. The tumor microenvironment (TME) is a major constituent of tumors and a key modulator of their behavior. Multiple cellular and secretory components of the TME dictate the development and metastasis of tumors. Immune cells like macrophages, natural killer (NK) cells, dendritic cells, B and T lymphocytes are a part of the tumor "immune" microenvironment (TIME). The expression of the Tn and STn antigens on tumors has been found to regulate the function of these immune cells and alter their normal antitumor cytotoxic role. This is possible through multiple cell intrinsic and extrinsic signaling pathways, elaborated in this review. Studying the interaction between Tn/STn antigens and the TIME of gastrointestinal cancers can help develop better and more robust therapies that can counteract immunosuppressive mechanisms to sensitize these tumors to anticancer therapies.
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Affiliation(s)
- Christabelle Rajesh
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, United States
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, United States
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16
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A roadmap for translational cancer glycoimmunology at single cell resolution. J Exp Clin Cancer Res 2022; 41:143. [PMID: 35428302 PMCID: PMC9013178 DOI: 10.1186/s13046-022-02335-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 03/17/2022] [Indexed: 11/11/2022] Open
Abstract
Cancer cells can evade immune responses by exploiting inhibitory immune checkpoints. Immune checkpoint inhibitor (ICI) therapies based on anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have been extensively explored over the recent years to unleash otherwise compromised anti-cancer immune responses. However, it is also well established that immune suppression is a multifactorial process involving an intricate crosstalk between cancer cells and the immune systems. The cancer glycome is emerging as a relevant source of immune checkpoints governing immunosuppressive behaviour in immune cells, paving an avenue for novel immunotherapeutic options. This review addresses the current state-of-the-art concerning the role played by glycans controlling innate and adaptive immune responses, while shedding light on available experimental models for glycoimmunology. We also emphasize the tremendous progress observed in the development of humanized models for immunology, the paramount contribution of advances in high-throughput single-cell analysis in this context, and the importance of including predictive machine learning algorithms in translational research. This may constitute an important roadmap for glycoimmunology, supporting careful adoption of models foreseeing clinical translation of fundamental glycobiology knowledge towards next generation immunotherapies.
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17
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Huang J, Huang J, Zhang G. Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity. Cancers (Basel) 2022; 14:5840. [PMID: 36497322 PMCID: PMC9737300 DOI: 10.3390/cancers14235840] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/24/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Sialylation is an enzymatic process that covalently attaches sialic acids to glycoproteins and glycolipids and terminates them by creating sialic acid-containing glycans (sialoglycans). Sialoglycans, usually located in the outmost layers of cells, play crucial biological roles, notably in tumor transformation, growth, metastasis, and immune evasion. Thus, a deeper comprehension of sialylation in cancer will help to facilitate the development of innovative cancer therapies. Cancer sialylation-related articles have consistently increased over the last four years. The primary subjects of these studies are sialylation, cancer, immunotherapy, and metastasis. Tumor cells activate endothelial cells and metastasize to distant organs in part by the interactions of abnormally sialylated integrins with selectins. Furthermore, cancer sialylation masks tumor antigenic epitopes and induces an immunosuppressive environment, allowing cancer cells to escape immune monitoring. Cytotoxic T lymphocytes develop different recognition epitopes for glycosylated and nonglycosylated peptides. Therefore, targeting tumor-derived sialoglycans is a promising approach to cancer treatments for limiting the dissemination of tumor cells, revealing immunogenic tumor antigens, and boosting anti-cancer immunity. Exploring the exact tumor sialoglycans may facilitate the identification of new glycan targets, paving the way for the development of customized cancer treatments.
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Affiliation(s)
- Jianmei Huang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
| | - Jianming Huang
- Biochemistry and Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, China
| | - Guonan Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
- Department of Gynecologic Oncology, Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
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18
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Concerted Regulation of Glycosylation Factors Sustains Tissue Identity and Function. Biomedicines 2022; 10:biomedicines10081805. [PMID: 36009354 PMCID: PMC9404854 DOI: 10.3390/biomedicines10081805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/27/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022] Open
Abstract
Glycosylation is a fundamental cellular process affecting human development and health. Complex machinery establishes the glycan structures whose heterogeneity provides greater structural diversity than other post-translational modifications. Although known to present spatial and temporal diversity, the evolution of glycosylation and its role at the tissue-specific level is poorly understood. In this study, we combined genome and transcriptome profiles of healthy and diseased tissues to uncover novel insights into the complex role of glycosylation in humans. We constructed a catalogue of human glycosylation factors, including transferases, hydrolases and other genes directly involved in glycosylation. These were categorized as involved in N-, O- and lipid-linked glycosylation, glypiation, and glycosaminoglycan synthesis. Our data showed that these glycosylation factors constitute an ancient family of genes, where evolutionary constraints suppressed large gene duplications, except for genes involved in O-linked and lipid glycosylation. The transcriptome profiles of 30 healthy human tissues revealed tissue-specific expression patterns preserved across mammals. In addition, clusters of tightly co-expressed genes suggest a glycosylation code underlying tissue identity. Interestingly, several glycosylation factors showed tissue-specific profiles varying with age, suggesting a role in ageing-related disorders. In cancer, our analysis revealed that glycosylation factors are highly perturbed, at the genome and transcriptome levels, with a strong predominance of copy number alterations. Moreover, glycosylation factor dysregulation was associated with distinct cellular compositions of the tumor microenvironment, reinforcing the impact of glycosylation in modulating the immune system. Overall, this work provides genome-wide evidence that the glycosylation machinery is tightly regulated in healthy tissues and impaired in ageing and tumorigenesis, unveiling novel potential roles as prognostic biomarkers or therapeutic targets.
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19
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Leite-Gomes E, Dias AM, Azevedo CM, Santos-Pereira B, Magalhães M, Garrido M, Amorim R, Lago P, Marcos-Pinto R, Pinho SS. Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player. Inflamm Bowel Dis 2022; 28:947-962. [PMID: 34849933 DOI: 10.1093/ibd/izab291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.
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Affiliation(s)
- Eduarda Leite-Gomes
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Ana M Dias
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Catarina M Azevedo
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Beatriz Santos-Pereira
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Mariana Magalhães
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Mónica Garrido
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Rita Amorim
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,Pediatrics Department, Centro Hospitalar e Universitário São João, Porto, Portugal.,Medical Faculty, University of Porto, Porto, Portugal
| | - Paula Lago
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Ricardo Marcos-Pinto
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal.,School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,Centre for Research in Health Technologies and Information Systems, University of Porto, Portugal
| | - Salomé S Pinho
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,Medical Faculty, University of Porto, Porto, Portugal
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20
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Berois N, Pittini A, Osinaga E. Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives. Cancers (Basel) 2022; 14:cancers14030645. [PMID: 35158915 PMCID: PMC8833780 DOI: 10.3390/cancers14030645] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Aberrant glycosylation is a common feature of many cancers, and it plays crucial roles in tumor development and biology. Cancer progression can be regulated by several physiopathological processes controlled by glycosylation, such as cell–cell adhesion, cell–matrix interaction, epithelial-to-mesenchymal transition, tumor proliferation, invasion, and metastasis. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs), which are suitable for selective cancer targeting, as well as novel antitumor immunotherapy approaches. This review summarizes the strategies developed in cancer immunotherapy targeting TACAs, analyzing molecular and cellular mechanisms and state-of-the-art methods in clinical oncology. Abstract Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.
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Affiliation(s)
- Nora Berois
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Correspondence: (N.B.); (E.O.)
| | - Alvaro Pittini
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Eduardo Osinaga
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Correspondence: (N.B.); (E.O.)
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21
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Kumar AR, Devan AR, Nair B, Nair RR, Nath LR. Biology, Significance and Immune Signaling of Mucin 1 in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2022; 22:725-740. [PMID: 35301949 DOI: 10.2174/1568009622666220317090552] [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: 09/16/2021] [Revised: 12/14/2021] [Accepted: 12/21/2021] [Indexed: 02/08/2023]
Abstract
Mucin 1 (MUC 1) is a highly glycosylated tumor-associated antigen (TAA) overexpressed in hepatocellular carcinoma (HCC). This protein plays a critical role in various immune-mediated signaling pathways at its transcriptional and post-transcriptional levels, leading to immune evasion and metastasis in HCC. HCC cells maintain an immune-suppressive environment with the help of immunesuppressive tumor-associated antigens, resulting in a metastatic spread of the disease. The development of intense immunotherapeutic strategies to target tumor-associated antigen is critical to overcoming the progression of HCC. MUC 1 remains the most recognized tumor-associated antigen since its discovery over 30 years ago. A few promising immunotherapies targeting MUC 1 are currently under clinical trials, including CAR-T and CAR-pNK-mediated therapies. This review highlights the biosynthesis, significance, and clinical implication of MUC 1 as an immune target in HCC.
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Affiliation(s)
- Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Aswathy R Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | | | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
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22
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Zhang Y, Wang L, Ocansey DKW, Wang B, Wang L, Xu Z. Mucin-Type O-Glycans: Barrier, Microbiota, and Immune Anchors in Inflammatory Bowel Disease. J Inflamm Res 2021; 14:5939-5953. [PMID: 34803391 PMCID: PMC8598207 DOI: 10.2147/jir.s327609] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/19/2021] [Indexed: 12/21/2022] Open
Abstract
Inflammatory bowel disease (IBD), which affects about 7 million people globally, is a chronic inflammatory condition of the gastrointestinal tract caused by gut microbiota alterations, immune dysregulation, and genetic and environmental factors. The association of microbial and immune molecules with mucin-type O-glycans has been increasingly noticed by researchers. Mucin is the main component of mucus, which forms a protective barrier between the microbiota and immune cells in the colon. Mucin-type O-glycans alter the diversity of gastrointestinal microorganisms, which in turn increases the level of O-glycosylation of host intestinal proteins via the utilization of glycans. Additionally, alterations in mucin-type O-glycans not only increase the activity and stability of immune cells but are also involved in the maintenance of intestinal mucosal immune tolerance. Although there is accumulating evidence indicating that mucin-type O-glycans play an important role in IBD, there is limited literature that integrates available data to present a complete picture of exactly how O-glycans affect IBD. This review emphasizes the roles of the mucin-type O-glycans in IBD. This seeks to provide a better understanding and encourages future studies on IBD glycosylation and the design of novel glycan-inspired therapies for IBD.
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Affiliation(s)
- Yaqin Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Lan Wang
- Danyang Blood Station, Zhenjiang, Jiangsu, 212300, People's Republic of China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China.,Directorate of University Health Services, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Bo Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Li Wang
- Huai'an Maternity and Children Hospital, Huaian, Jiangsu, 223002, People's Republic of China
| | - Zhiwei Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
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23
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The T/Tn-Specific Helix pomatia Lectin Induces Cell Death in Lymphoma Cells Negative for T/Tn Antigens. Cancers (Basel) 2021; 13:cancers13174356. [PMID: 34503166 PMCID: PMC8431231 DOI: 10.3390/cancers13174356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Changes in glycosylation, such as incomplete synthesis and higher density of O-glycans on the cell surface, are frequently observed in cancer cells. Several types of truncated O-glycan structures, e.g., T/Tn antigens, are suspected to disrupt molecular interactions between tumor microenvironment and immune cells, for instance, facilitating cancer immune-escape. Therefore, numerous exogenous lectins targeting aberrant O-glycans are interesting tools for cancer diagnosis, prognosis, and therapy. However, the ability of exolectins to detect subtle alterations in the glycome of tumor cells and to interfere in tumor/healthy cell interactions remains largely unknown. The present article reports for the first time that the Helix pomatia (HPA) lectin, a well-known T/Tn-specific lectin, currently used as a tool in cancer diagnostics, kills Tn-positive leukemia cells and Tn-negative lymphoma cells but does not affect healthy lymphocytes. Thus, HPA could be used to discriminate between tumor and healthy cells, and detect subtle alterations in the glycosylation profile. Abstract Morniga G is a T/Tn-specific lectin, inducing cell death in Tn-positive leukemias but not in healthy lymphocytes. Helix pomatia lectin (HPA) is another T/Tn-specific lectin, currently used as tool for cancer diagnostics. The HPA-mediated tumor cell death was evaluated on human leukemia and mouse lymphoma cells, and compared to the effect of Morniga G. Both lectins induced an equivalent percentage of cell death in Tn-positive Jurkat human leukemia. In contrast, EL4 mouse lymphoma resisted Morniga G-mediated cytotoxicity but were killed by HPA at concentrations of 2.5 μg/mL (0.032 nM) and higher. In both malignant cells, HPA-mediated cell death showed features compatible with apoptosis (annexin-externalization, caspase-activation, mitochondrial membrane depolarization, and ROS production). Cytometry analysis indicated that EL4 cells are T/Tn-negative. Because previous results showed a high amount of N-acetylgalactosamine (GalNAc, sugar present in Tn antigen) on EL4 cell surface, this GalNAc could be involved in the formation of truncated O-glycans other than the T/Tn residues. When compared to Morniga G, bioinformatic analysis suggested that HPA benefits from an extended carbohydrate-binding site, better adapted than Morniga G to the accommodation of more complex branched and truncated O-glycans (such as core 2). Finally, HPA killed EL4 cells but not healthy lymphocytes in a mixture of lymphoma cells + lymphocytes, suggesting that HPA selectively triggers tumor cell death.
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Xu F, Zhao H, Li J, Jiang H. Mucin-type sialyl-Tn antigen is associated with PD-L1 expression and predicts poor clinical prognosis in breast cancer. Gland Surg 2021; 10:2159-2169. [PMID: 34422587 DOI: 10.21037/gs-21-83] [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] [Received: 02/07/2021] [Accepted: 05/21/2021] [Indexed: 11/06/2022]
Abstract
Background A recent study showed that mucin-type sialylated O-linked glycans could induce the increased expression of PD-L1 via binding to Siglec receptors. However, the relationship between the expression of the mucin-type sialyl-Tn antigen (sTn) and PD-L1 remains unclear in breast cancer (BC). Therefore, we investigate the clinicopathological and prognostic effects of sTn expression and its relationship with PD-L1 expression in BC tissues. Methods We retrospectively analyzed the clinical data of 380 invasive BC patients between January 2011 and January 2014. The last follow-up time was January 31, 2019 with a median follow-up of 62 months. The expression of the sTn antigen and PD-L1 in 380 tumor specimens was assessed by immunohistochemistry. Correlations between sTn/PD-L1 expression and clinicopathological features and prognoses were analyzed. Results In BC tissues, the positive expression rate of PD-L1 (20.5%) was much lower than that of sTn (41.8%). Pearson's contingency analysis showed that sTn and PD-L1 expression in tumor tissues demonstrated a high correlation (P<0.001). High sTn expression was associated with negative ER expression (P<0.001), positive HER-2 status (P<0.001), advanced tumor stage (P<0.001), high density of CD8+ tumor-infiltrating lymphocytes (TILs) (P=0.028), and positive lymph node metastasis (P=0.002). Moreover, patients with concomitant high expression of both markers had the highest risk of relapse (P<0.001) and mortality (P<0.001). The multivariate Cox regression model revealed that positive sTn expression (HRos: 1.941, 95% CI: 1.168, 3.223, Pos=0.028; HRpfs: 1.739, 95% CI: 1.063, 2.847, Ppfs=0.010) and positive PD-L1 expression (HRos: 1.912, 95% CI: 1.138, 3.212, Pos=0.017; HRpfs: 1.863, 95% CI: 1.116, 3.110, Ppfs=0.014) were independent indicators for poor overall survival (OS) and progression-free survival (PFS), respectively. Conclusions BC patients who expressed both sTn and PD-L1 had poorer survival. Therefore, combinational therapy with dual blockade might benefit BC patients with sTn(+)/PD-L1(+) expression, which requires further examination in future clinical trials.
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Affiliation(s)
- Feng Xu
- Department of Breast Surgery, Beijing Chao-Yang Hospital, Beijing, China
| | - Hongying Zhao
- Department of Pathology, Beijing Chao-Yang Hospital, Beijing, China
| | - Jie Li
- Department of Breast Surgery, Beijing Chao-Yang Hospital, Beijing, China
| | - Hongchuan Jiang
- Department of Breast Surgery, Beijing Chao-Yang Hospital, Beijing, China
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25
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López-Cortés R, Gómez BB, Vázquez-Estévez S, Pérez-Fentes D, Núñez C. Blood-based protein biomarkers in bladder urothelial tumors. J Proteomics 2021; 247:104329. [PMID: 34298186 DOI: 10.1016/j.jprot.2021.104329] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 07/15/2021] [Indexed: 12/16/2022]
Abstract
Bladder cancer (BC) is the fifth most common cancer with a high prevalence rate. It is classically classified in two groups, namely non-muscle invasive (NMIBC) and muscle invasive (MIBC). NMIBC accounts for 75% of cases and has a better prognosis than MIBC. However, 30-50% of the NMIBC patients will show recurrences throughout their lives, and about 10-20% of them will progress to MIBC, with frequent metastasis and a reduced survival rate. The diagnosis of bladder cancer is confirmed by direct visualization of the tumour and other mucosal abnormalities with endoscopic excision using cystoscopy and transurethral resection of the bladder (TURBT). An adequate TURBT requires complete resection of all visible tumour with appropriate sampling of the bladder to assess the depth of invasion. However, for many years, researchers have attempted to identify and utilise urinary markers for bladder cancer detection. Voided urine cytology has been the mainstay of urine-based diagnosis of bladder cancer since originally described by Papanicolau and Marshall. Nonetheless, urine cytology has several drawbacks, including a poor sensitivity for low-grade/stage tumours, a lack of interobserver consistency and a variable range of readings (e.g., atypical, atypical-suspicious, non-diagnostic). These shortcomings have inspired the search for more sensitive bladder cancer biomarkers. To bring precision medicine to genitourinary oncology, the analysis of the plasma/serum wide genome and proteome offers promising possibilities.
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Affiliation(s)
- Rubén López-Cortés
- Research Unit, Hospital Universitario Lucus Augusti (HULA), Servizo Galego de Saúde (SERGAS), ES27002 Lugo, Spain
| | - Benito Blanco Gómez
- Urology Division, Hospital Universitario Lucus Augusti (HULA), Servizo Galego de Saúde (SERGAS), ES27002, Lugo, Spain
| | - Sergio Vázquez-Estévez
- Oncology Division, Hospital Universitario Lucus Augusti (HULA), Servizo Galego de Saúde (SERGAS), ES27002 Lugo, Spain
| | - Daniel Pérez-Fentes
- Urology Division, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), ES15706 Santiago de Compostela, Spain
| | - Cristina Núñez
- Research Unit, Hospital Universitario Lucus Augusti (HULA), Servizo Galego de Saúde (SERGAS), ES27002 Lugo, Spain.
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Peixoto A, Ferreira D, Azevedo R, Freitas R, Fernandes E, Relvas-Santos M, Gaiteiro C, Soares J, Cotton S, Teixeira B, Paulo P, Lima L, Palmeira C, Martins G, Oliveira MJ, Silva AMN, Santos LL, Ferreira JA. Glycoproteomics identifies HOMER3 as a potentially targetable biomarker triggered by hypoxia and glucose deprivation in bladder cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:191. [PMID: 34108014 PMCID: PMC8188679 DOI: 10.1186/s13046-021-01988-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/17/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND Muscle invasive bladder cancer (MIBC) remains amongst the deadliest genitourinary malignancies due to treatment failure and extensive molecular heterogeneity, delaying effective targeted therapeutics. Hypoxia and nutrient deprivation, oversialylation and O-glycans shortening are salient features of aggressive tumours, creating cell surface glycoproteome fingerprints with theranostics potential. METHODS A glycomics guided glycoproteomics workflow was employed to identify potentially targetable biomarkers using invasive bladder cancer cell models. The 5637 and T24 cells O-glycome was characterized by mass spectrometry (MS), and the obtained information was used to guide glycoproteomics experiments, combining sialidase, lectin affinity and bottom-up protein identification by nanoLC-ESI-MS/MS. Data was curated by a bioinformatics approach developed in-house, sorting clinically relevant molecular signatures based on Human Protein Atlas insights. Top-ranked targets and glycoforms were validated in cell models, bladder tumours and metastases by MS and immunoassays. Cells grown under hypoxia and glucose deprivation disclosed the contribution of tumour microenvironment to the expression of relevant biomarkers. Cancer-specificity was validated in healthy tissues by immunohistochemistry and MS in 20 types of tissues/cells of different individuals. RESULTS Sialylated T (ST) antigens were found to be the most abundant glycans in cell lines and over 900 glycoproteins were identified potentially carrying these glycans. HOMER3, typically a cytosolic protein, emerged as a top-ranked targetable glycoprotein at the cell surface carrying short-chain O-glycans. Plasma membrane HOMER3 was observed in more aggressive primary tumours and distant metastases, being an independent predictor of worst prognosis. This phenotype was triggered by nutrient deprivation and concomitant to increased cellular invasion. T24 HOMER3 knockdown significantly decreased proliferation and, to some extent, invasion in normoxia and hypoxia; whereas HOMER3 knock-in increased its membrane expression, which was more pronounced under glucose deprivation. HOMER3 overexpression was associated with increased cell proliferation in normoxia and potentiated invasion under hypoxia. Finally, the mapping of HOMER3-glycosites by EThcD-MS/MS in bladder tumours revealed potentially targetable domains not detected in healthy tissues. CONCLUSION HOMER3-glycoforms allow the identification of patients' subsets facing worst prognosis, holding potential to address more aggressive hypoxic cells with limited off-target effects. The molecular rationale for identifying novel bladder cancer molecular targets has been established.
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Affiliation(s)
- Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135, Porto, Portugal.,Institute for Biomedical Engineering (INEB), University of Porto, 4200-135, Porto, Portugal
| | - Dylan Ferreira
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135, Porto, Portugal.,Institute for Biomedical Engineering (INEB), University of Porto, 4200-135, Porto, Portugal
| | - Rita Azevedo
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal
| | - Rui Freitas
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal
| | - Elisabete Fernandes
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135, Porto, Portugal.,Institute for Biomedical Engineering (INEB), University of Porto, 4200-135, Porto, Portugal
| | - Marta Relvas-Santos
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135, Porto, Portugal.,Institute for Biomedical Engineering (INEB), University of Porto, 4200-135, Porto, Portugal.,REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Porto, 4169-007, Porto, Portugal
| | - Cristiana Gaiteiro
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal
| | - Janine Soares
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal
| | - Sofia Cotton
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal
| | - Beatriz Teixeira
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal
| | - Paula Paulo
- Cancer Genetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072, Porto, Portugal
| | - Luís Lima
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal
| | - Carlos Palmeira
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Immunology Department, Portuguese Institute of Oncology of Porto, 4200-072, Porto, Portugal.,Health School of University Fernando Pessoa, 4249-004, Porto, Portugal
| | - Gabriela Martins
- Immunology Department, Portuguese Institute of Oncology of Porto, 4200-072, Porto, Portugal
| | - Maria José Oliveira
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135, Porto, Portugal.,Institute for Biomedical Engineering (INEB), University of Porto, 4200-135, Porto, Portugal
| | - André M N Silva
- REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Porto, 4169-007, Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal.,Health School of University Fernando Pessoa, 4249-004, Porto, Portugal.,Department of Surgical Oncology, Portuguese Institute of Oncology, 4200-072, Porto, Portugal.,Porto Comprehensive Cancer Center (P.ccc), 4200-072, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal. .,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313, Porto, Portugal. .,Porto Comprehensive Cancer Center (P.ccc), 4200-072, Porto, Portugal.
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Cotton S, Ferreira D, Soares J, Peixoto A, Relvas-Santos M, Azevedo R, Piairo P, Diéguez L, Palmeira C, Lima L, Silva AMN, Lara Santos L, Ferreira JA. Target Score-A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness. Int J Mol Sci 2021; 22:ijms22041664. [PMID: 33562270 PMCID: PMC7915893 DOI: 10.3390/ijms22041664] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/28/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer (EC) is a life-threatening disease, demanding the discovery of new biomarkers and molecular targets for precision oncology. Aberrantly glycosylated proteins hold tremendous potential towards this objective. In the current study, a series of esophageal squamous cell carcinomas (ESCC) and EC-derived circulating tumor cells (CTCs) were screened by immunoassays for the sialyl-Tn (STn) antigen, a glycan rarely expressed in healthy tissues and widely observed in aggressive gastrointestinal cancers. An ESCC cell model was glycoengineered to express STn and characterized in relation to cell proliferation and invasion in vitro. STn was found to be widely present in ESCC (70% of tumors) and in CTCs in 20% of patients, being associated with general recurrence and reduced survival. Furthermore, STn expression in ESCC cells increased invasion in vitro, while reducing cancer cells proliferation. In parallel, an ESCC mass spectrometry-based proteomics dataset, obtained from the PRIDE database, was comprehensively interrogated for abnormally glycosylated proteins. Data integration with the Target Score, an algorithm developed in-house, pinpointed the glucose transporter type 1 (GLUT1) as a biomarker of poor prognosis. GLUT1-STn glycoproteoforms were latter identified in tumor tissues in patients facing worst prognosis. Furthermore, healthy human tissues analysis suggested that STn glycosylation provided cancer specificity to GLUT1. In conclusion, STn is a biomarker of worst prognosis in EC and GLUT1-STn glycoforms may be used to increase its specificity on the stratification and targeting of aggressive ESCC forms.
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Affiliation(s)
- Sofia Cotton
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
- Institute for Biomedical Engineering (INEB), 4200-135 Porto, Portugal
| | - Dylan Ferreira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
- Institute for Biomedical Engineering (INEB), 4200-135 Porto, Portugal
| | - Janine Soares
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- QOPNA/LAQV, Department of Chemistry, Campus Universitário de Santiago, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
- Institute for Biomedical Engineering (INEB), 4200-135 Porto, Portugal
| | - Marta Relvas-Santos
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
- Institute for Biomedical Engineering (INEB), 4200-135 Porto, Portugal
- REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal;
| | - Rita Azevedo
- Institute of Biomedicine, University of Turku, FI-20014 Turku, Finland;
| | - Paulina Piairo
- Medical Devices Research Group, International Iberian Nanotechnology Laboratory (INL), 4715-330 Braga, Portugal; (P.P.); (L.D.)
| | - Lorena Diéguez
- Medical Devices Research Group, International Iberian Nanotechnology Laboratory (INL), 4715-330 Braga, Portugal; (P.P.); (L.D.)
| | - Carlos Palmeira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Department of Immunology, Portuguese Institute of Oncology of Porto, 4200-072 Porto, Portugal
- Health Science Faculty, University of Fernando Pessoa, 4249-004 Porto, Portugal
| | - Luís Lima
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal
| | - André M. N. Silva
- REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal;
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Health Science Faculty, University of Fernando Pessoa, 4249-004 Porto, Portugal
- Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal
- Department of Surgical Oncology, Portuguese Institute of Oncology, 4200-072 Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute (IPO Porto), 4200-072 Porto, Portugal; (S.C.); (D.F.); (J.S.); (A.P.); (M.R.-S.); (C.P.); (L.L.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal
- Correspondence: ; Tel.: +351-225-084-000 (ext. 5111)
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Calmeiro J, Mendes L, Duarte IF, Leitão C, Tavares AR, Ferreira DA, Gomes C, Serra J, Falcão A, Cruz MT, Carrascal MA, Neves BM. In-Depth Analysis of the Impact of Different Serum-Free Media on the Production of Clinical Grade Dendritic Cells for Cancer Immunotherapy. Front Immunol 2021; 11:593363. [PMID: 33613517 PMCID: PMC7893095 DOI: 10.3389/fimmu.2020.593363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/17/2020] [Indexed: 12/15/2022] Open
Abstract
Dendritic cell (DC)-based antitumor vaccines have proven to be a safe approach, but often fail to generate robust results between trials. Translation to the clinic has been hindered in part by the lack of standard operation procedures for vaccines production, namely the definition of optimal culture conditions during ex-vivo DC differentiation. Here we sought to compare the ability of three clinical grade serum-free media, DendriMACS, AIM-V, and X-VIVO 15, alongside with fetal bovine serum-supplemented Roswell Park Memorial Institute Medium (RPMI), to support the differentiation of monocyte-derived DCs (Mo-DCs). Under these different culture conditions, phenotype, cell metabolomic profiles, response to maturation stimuli, cytokines production, allogenic T cell stimulatory capacity, as well as priming of antigen-specific CD8+ T cells and activation of autologous natural killer (NK) cells were analyzed. Immature Mo-DCs differentiated in AIM-V or X-VIVO 15 presented lower levels of CD1c, CD1a, and higher expression of CD11c, when compared to cells obtained with DendriMACS. Upon stimulation, only AIM-V or X-VIVO 15 DCs acquired a full mature phenotype, which supports their enhanced capacity to polarize T helper cell type 1 subset, to prime antigen-specific CD8+ T cells and to activate NK cells. CD8+ T cells and NK cells resulting from co-culture with AIM-V or X-VIVO 15 DCs also showed superior cytolytic activity. 1H nuclear magnetic resonance-based metabolomic analysis revealed that superior DC immunostimulatory capacities correlate with an enhanced catabolism of amino acids and glucose. Overall, our data highlight the impact of critically defining the culture medium used in the production of DCs for clinical application in cancer immunotherapy. Moreover, the manipulation of metabolic state during differentiation could be envisaged as a strategy to enhance desired cell characteristics.
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Affiliation(s)
- João Calmeiro
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Luís Mendes
- CICECO, Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Iola F Duarte
- CICECO, Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Catarina Leitão
- Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
| | - Adriana R Tavares
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Daniel Alexandre Ferreira
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Célia Gomes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
| | | | - Amílcar Falcão
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Coimbra, Portugal
| | - Maria Teresa Cruz
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | | | - Bruno Miguel Neves
- Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
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Sun J, Lu Q, Sanmamed MF, Wang J. Siglec-15 as an Emerging Target for Next-generation Cancer Immunotherapy. Clin Cancer Res 2021; 27:680-688. [PMID: 32958700 PMCID: PMC9942711 DOI: 10.1158/1078-0432.ccr-19-2925] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/07/2020] [Accepted: 09/16/2020] [Indexed: 01/21/2023]
Abstract
Immunomodulatory agents blocking the PD-1/PD-L1 pathway have shown a new way to treat cancer. The explanation underlying the success of these agents may be the selective expression of PD-L1 with dominant immune-suppressive activities in the tumor microenvironment (TME), supporting a more favorable tumor response-to-toxicity ratio. However, despite the big success of these drugs, most patients with cancer show primary or acquired resistance, calling for the identification of new immune modulators in the TME. Using a genome-scale T-cell activity array in combination with bioinformatic analysis of human cancer databases, we identified Siglec-15 as a critical immune suppressor with broad upregulation on various cancer types and a potential target for cancer immunotherapy. Siglec-15 has unique molecular features compared with many other known checkpoint inhibitory ligands. It shows prominent expression on macrophages and cancer cells and a mutually exclusive expression with PD-L1, suggesting that it may be a critical immune evasion mechanism in PD-L1-negative patients. Interestingly, Siglec-15 has also been identified as a key regulator for osteoclast differentiation and may have potential implications in bone disorders not limited to osteoporosis. Here, we provide an overview of Siglec-15 biology, its role in cancer immune regulation, the preliminary and encouraging clinical data related to the first-in-class Siglec-15 targeting mAb, as well as many unsolved questions in this pathway. As a new player in the cancer immunotherapeutic arena, Siglec-15 may represent a novel class of immune inhibitors with tumor-associated expression and divergent mechanisms of action to PD-L1, with potential implications in anti-PD-1/PD-L1-resistant patients.
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Affiliation(s)
- Jingwei Sun
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut
| | - Qiao Lu
- Department of Pathology, New York University Grossman School of Medicine, New York, New York
- The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York
| | - Miguel F Sanmamed
- Program of Immunology and Immunotherapy, CIMA, University of Navarra, Pamplona, Spain
| | - Jun Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, New York.
- The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York
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30
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Wu YX, Lu HF, Lin YH, Chuang HY, Su SC, Liao YJ, Twu YC. Branched I antigen regulated cell susceptibility against natural killer cytotoxicity through its N-linked glycosylation and overall expression. Glycobiology 2021; 31:624-635. [PMID: 33403394 DOI: 10.1093/glycob/cwaa117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/27/2020] [Accepted: 12/16/2020] [Indexed: 11/14/2022] Open
Abstract
Cell surface glycosylation has been known as an important modification process that can be targeted and manipulated by malignant cells to escape from host immunosurveillance. We previously showed that the blood group branched I antigen on the leukemia cell surface can regulate the cell susceptibility against natural killer (NK) cell-mediated cytotoxicity through interfering target-NK interaction. In this work, we first identified N-linkage as the major glycosylation linkage type for branched I glycan formation on leukemia cells, and this linkage was responsible for cell sensitivity against therapeutic NK-92MI targeting. Secondly, by examining different leukemia cell surface death receptors, we showed death receptor Fas had highest expressions in both Raji and TF-1a cells. Mutations on two Fas extracellular N-linkage sites (118 and 136) for glycosylation impaired activation of Fas-mediated apoptosis during NK-92MI cytotoxicity. Last, we found that the surface I antigen expression levels enable leukemia cells to respond differently against NK-92MI targeting. In low I antigen expressing K-562 cell, reduction of I antigen presence greatly reduced leukemia cell susceptibility against NK-92MI targeting. But in other high I antigen expressing leukemia cells, similar reduction in I antigen expression did not affect cell susceptibility.
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Affiliation(s)
- Yu-Xuan Wu
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, 155, Sec. 2, Li-Nong-St., Taipei, 112, Taiwan
| | - Hsu-Feng Lu
- Department of Clinical Pathology, Cheng Hsin General Hospital, 45, Cheng-Hsin St., Taipei, 112, Taiwan.,Department of Restaurant, Hotel and Institutional Management, Fu-Jen Catholic University, 510, Zhongzheng Rd., New Taipei City, 242, Taiwan
| | - Yen-Hsi Lin
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, 155, Sec. 2, Li-Nong-St., Taipei, 112, Taiwan.,Department of Clinical Laboratory, Chung Shan Medical University Hospital, 110, Sec. 1, Jianguo N. Rd., Taichung City, 402, Taiwan
| | - Hui-Yu Chuang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, 155, Sec. 2, Li-Nong-St., Taipei, 112, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, 222, Maijin Rd., Keelung City, 204, Taiwan.,Central Research Laboratory, Xiamen Chang Gung Hospital, 123, Xiafei Rd., Haicang District, Xiamen, China
| | - Yi-Jen Liao
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan
| | - Yuh-Ching Twu
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, 155, Sec. 2, Li-Nong-St., Taipei, 112, Taiwan
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31
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Li CF, Liang PI, Chan TC, Shiue YL. Molecular biology of urothelial carcinoma. JOURNAL OF CANCER RESEARCH AND PRACTICE 2021. [DOI: 10.4103/jcrp.jcrp_1_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Peixoto A, Cotton S, Santos LL, Ferreira JA. The Tumour Microenvironment and Circulating Tumour Cells: A Partnership Driving Metastasis and Glycan-Based Opportunities for Cancer Control. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:1-33. [PMID: 34664231 DOI: 10.1007/978-3-030-73119-9_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Circulating tumour cells (CTC) are rare cells that actively detach or are shed from primary tumours into the lymph and blood. Some CTC subpopulations gain the capacity to survive, home and colonize distant locations, forming metastasis. This results from a multifactorial process in which cancer cells optimize motility, invasion, immune escape and cooperative relationships with microenvironmental cues. Here we present evidences of a self-fuelling molecular crosstalk between cancer cells and the tumour stroma supporting the main milestones leading to metastasis. We discuss how the tumour microenvironment supports pre-metastatic niches and CTC development and ultimately dictates CTC fate in targeted organs. Finally, we highlight the key role played by protein glycosylation in metastasis development, its prompt response to microenvironmental stimuli and the tremendous potential of glycan-based molecular signatures for liquid biopsies and targeted therapeutics.
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Affiliation(s)
- Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal. .,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal. .,Institute for Research and Innovation in Health (i3s), University of Porto, Porto, Portugal. .,Institute for Biomedical Engineering (INEB), Porto, Portugal. .,Porto Comprehensive Cancer Centre (P.ccc), Porto, Portugal.
| | - Sofia Cotton
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Institute for Research and Innovation in Health (i3s), University of Porto, Porto, Portugal.,Institute for Biomedical Engineering (INEB), Porto, Portugal.,Porto Comprehensive Cancer Centre (P.ccc), Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Porto Comprehensive Cancer Centre (P.ccc), Porto, Portugal.,Department of Surgical Oncology, Portuguese Institute of Oncology of Porto, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.,Porto Comprehensive Cancer Centre (P.ccc), Porto, Portugal
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Deschepper FM, Zoppi R, Pirro M, Hensbergen PJ, Dall’Olio F, Kotsias M, Gardner RA, Spencer DI, Videira PA. L1CAM as an E-selectin Ligand in Colon Cancer. Int J Mol Sci 2020; 21:ijms21218286. [PMID: 33167483 PMCID: PMC7672641 DOI: 10.3390/ijms21218286] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Metastasis is the main cause of death among colorectal cancer (CRC) patients. E-selectin and its carbohydrate ligands, including sialyl Lewis X (sLeX) antigen, are key players in the binding of circulating tumor cells to the endothelium, which is one of the major events leading to organ invasion. Nevertheless, the identity of the glycoprotein scaffolds presenting these glycans in CRC remains unclear. In this study, we firstly have characterized the glycoengineered cell line SW620 transfected with the fucosyltransferase 6 (FUT6) coding for the α1,3-fucosyltransferase 6 (FUT6), which is the main enzyme responsible for the synthesis of sLeX in CRC. The SW620FUT6 cell line expressed high levels of sLeX antigen and E-selectin ligands. Moreover, it displayed increased migration ability. E-selectin ligand glycoproteins were isolated from the SW620FUT6 cell line, identified by mass spectrometry, and validated by flow cytometry and Western blot (WB). The most prominent E-selectin ligand we identified was the neural cell adhesion molecule L1 (L1CAM). Previous studies have shown association of L1CAM with metastasis in cancer, thus the novel role as E-selectin counter-receptor contributes to understand the molecular mechanism involving L1CAM in metastasis formation.
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Affiliation(s)
- Fanny M. Deschepper
- Unidade de Ciências Biomoleculares Aplicadas (UCIBIO), Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (F.M.D.); (R.Z.)
| | - Roberta Zoppi
- Unidade de Ciências Biomoleculares Aplicadas (UCIBIO), Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (F.M.D.); (R.Z.)
| | - Martina Pirro
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (M.P.); (P.J.H.)
| | - Paul J. Hensbergen
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (M.P.); (P.J.H.)
| | - Fabio Dall’Olio
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy;
| | - Maximillianos Kotsias
- Ludger Ltd., Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, UK; (M.K.); (R.A.G.); (D.I.R.S.)
| | - Richard A. Gardner
- Ludger Ltd., Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, UK; (M.K.); (R.A.G.); (D.I.R.S.)
| | - Daniel I.R. Spencer
- Ludger Ltd., Culham Science Centre, Abingdon, Oxfordshire OX14 3EB, UK; (M.K.); (R.A.G.); (D.I.R.S.)
| | - Paula A. Videira
- Unidade de Ciências Biomoleculares Aplicadas (UCIBIO), Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (F.M.D.); (R.Z.)
- CDG & Allies - Professionals and Patient Associations International Network (CDG & Allies - PPAIN), 2829-516 Caparica, Portugal
- Correspondence:
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34
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Jian Y, Xu Z, Xu C, Zhang L, Sun X, Yang D, Wang S. The Roles of Glycans in Bladder Cancer. Front Oncol 2020; 10:957. [PMID: 32596162 PMCID: PMC7303958 DOI: 10.3389/fonc.2020.00957] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/15/2020] [Indexed: 11/13/2022] Open
Abstract
Bladder cancer is one of the most common malignant tumors of the urogenital system with high morbidity and mortality worldwide. Early diagnosis and personalized treatment are the keys to successful bladder cancer treatment. Due to high postoperative recurrence rates and poor prognosis, it is urgent to find suitable therapeutic targets and biomarkers. Glycans are one of the four biological macromolecules in the cells of an organism, along with proteins, nucleic acids, and lipids. Glycans play important roles in nascent peptide chain folding, protein processing, and translation, cell-to-cell adhesion, receptor-ligand recognition, and binding and cell signaling. Glycans are mainly divided into N-glycans, O-glycans, proteoglycans, and glycosphingolipids. The focus of this review is the discussion of glycans related to bladder cancer. Additionally, this review also addresses the clinical value of glycans in the diagnosis and treatment of bladder cancer. Abnormal glycans are likely to be potential biomarkers for bladder cancer.
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Affiliation(s)
- Yuli Jian
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Zhongyang Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Chunyan Xu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Lin Zhang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Xiaoxin Sun
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
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35
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Loureiro LR, Feldmann A, Bergmann R, Koristka S, Berndt N, Máthé D, Hegedüs N, Szigeti K, Videira PA, Bachmann M, Arndt C. Extended half-life target module for sustainable UniCAR T-cell treatment of STn-expressing cancers. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:77. [PMID: 32370811 PMCID: PMC7201957 DOI: 10.1186/s13046-020-01572-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022]
Abstract
Background Adapter chimeric antigen receptor (CAR) approaches have emerged has promising strategies to increase clinical safety of CAR T-cell therapy. In the UniCAR system, the safety switch is controlled via a target module (TM) which is characterized by a small-size and short half-life. The rapid clearance of these TMs from the blood allows a quick steering and self-limiting safety switch of UniCAR T-cells by TM dosing. This is mainly important during onset of therapy when tumor burden and the risk for severe side effects are high. For long-term UniCAR therapy, the continuous infusion of TMs may not be an optimal setting for the patients. Thus, in later stages of treatment, single infusions of TMs with an increased half-life might play an important role in long-term surveillance and eradication of residual tumor cells. Given this, we aimed to develop and characterize a novel TM with extended half-life targeting the tumor-associated carbohydrate sialyl-Tn (STn). Methods The extended half-life TM is composed of the STn-specific single-chain variable fragment (scFv) and the UniCAR epitope, fused to the hinge region and Fc domain of a human immunoglobulin 4 (IgG4) antibody. Specific binding and functionality of the αSTn-IgG4 TM as well as pharmacokinetic features were assessed using in vitro and in vivo assays and compared to the already established small-sized αSTn TM. Results The novel αSTn-IgG4 TM efficiently activates and redirects UniCAR T-cells to STn-expressing tumors in a target-specific and TM-dependent manner, thereby promoting the secretion of proinflammatory cytokines and tumor cell lysis in vitro and in experimental mice. Moreover, PET-imaging results demonstrate the specific enrichment of the αSTn-IgG4 TM at the tumor site, while presenting a prolonged serum half-life compared to the short-lived αSTn TM. Conclusion In a clinical setting, the combination of TMs with different formats and pharmacokinetics may represent a promising strategy for retargeting of UniCAR T-cells in a flexible, individualized and safe manner at particular stages of therapy. Furthermore, as these molecules can be used for in vivo imaging, they pose as attractive candidates for theranostic approaches.
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Affiliation(s)
- Liliana R Loureiro
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany.,National Center for Tumor Diseases (NCT), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Anja Feldmann
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany
| | - Ralf Bergmann
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany.,Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Stefanie Koristka
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany
| | - Nicole Berndt
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany
| | - Domokos Máthé
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Nikolett Hegedüs
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Krisztián Szigeti
- Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Paula A Videira
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal
| | - Michael Bachmann
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany. .,National Center for Tumor Diseases (NCT), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany. .,German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Tumor Immunology, University CancerCenter (UCC), University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
| | - Claudia Arndt
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328, Dresden, Germany
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Fernandes E, Sores J, Cotton S, Peixoto A, Ferreira D, Freitas R, Reis CA, Santos LL, Ferreira JA. Esophageal, gastric and colorectal cancers: Looking beyond classical serological biomarkers towards glycoproteomics-assisted precision oncology. Am J Cancer Res 2020; 10:4903-4928. [PMID: 32308758 PMCID: PMC7163443 DOI: 10.7150/thno.42480] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/16/2020] [Indexed: 12/24/2022] Open
Abstract
Esophageal (OC), gastric (GC) and colorectal (CRC) cancers are amongst the digestive track tumors with higher incidence and mortality due to significant molecular heterogeneity. This constitutes a major challenge for patients' management at different levels, including non-invasive detection of the disease, prognostication, therapy selection, patient's follow-up and the introduction of improved and safer therapeutics. Nevertheless, important milestones have been accomplished pursuing the goal of molecular-based precision oncology. Over the past five years, high-throughput technologies have been used to interrogate tumors of distinct clinicopathological natures, generating large-scale biological datasets (e.g. genomics, transcriptomics, and proteomics). As a result, GC and CRC molecular subtypes have been established to assist patient stratification in the clinical settings. However, such molecular panels still require refinement and are yet to provide targetable biomarkers. In parallel, outstanding advances have been made regarding targeted therapeutics and immunotherapy, paving the way for improved patient care; nevertheless, important milestones towards treatment personalization and reduced off-target effects are also to be accomplished. Exploiting the cancer glycoproteome for unique molecular fingerprints generated by dramatic alterations in protein glycosylation may provide the necessary molecular rationale towards this end. Therefore, this review presents functional and clinical evidences supporting a reinvestigation of classical serological glycan biomarkers such as sialyl-Tn (STn) and sialyl-Lewis A (SLeA) antigens from a tumor glycoproteomics perspective. We anticipate that these glycobiomarkers that have so far been employed in non-invasive cancer prognostication may hold unexplored value for patients' management in precision oncology settings.
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Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans. Proc Natl Acad Sci U S A 2020; 117:7633-7644. [PMID: 32213588 DOI: 10.1073/pnas.1916498117] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.
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Molejon MI, Weiz G, Breccia JD, Vaccaro MI. Glycoconjugation: An approach to cancer therapeutics. World J Clin Oncol 2020; 11:110-120. [PMID: 32257842 PMCID: PMC7103525 DOI: 10.5306/wjco.v11.i3.110] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/31/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer constitutes the second leading cause of death globally and is considered to have been responsible for an estimated 9.6 million fatalities in 2018. Although treatments against gastrointestinal tumors have recently advanced, those interventions can only be applied to a minority of patients at the time of diagnosis. Therefore, new therapeutic options are necessary for advanced stages of the disease. Glycosylation of antitumor agents, has been found to improve pharmacokinetic parameters, reduce side effects, and expand drug half-life in comparison with the parent compounds. In addition, glycosylation of therapeutic agents has been proven to be an effective strategy for their targeting tumor tissue, thereby reducing the doses of the glycodrugs administered to patients. This review focusses on the effect of the targeting properties of glycosylated antitumor agents on gastrointestinal tumors.
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Affiliation(s)
- Maria I Molejon
- Institute of Earth and Environmental Sciences from La Pampa (INCITAP), National University of La Pampa, School of Natural Sciences (CONICET-UNLPam), Santa Rosa 6300, La Pampa, Argentina
- Institute of Biochemistry and Molecular Medicine (UBA-CONICET), Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - Gisela Weiz
- Institute of Earth and Environmental Sciences from La Pampa (INCITAP), National University of La Pampa, School of Natural Sciences (CONICET-UNLPam), Santa Rosa 6300, La Pampa, Argentina
| | - Javier D Breccia
- Institute of Earth and Environmental Sciences from La Pampa (INCITAP), National University of La Pampa, School of Natural Sciences (CONICET-UNLPam), Santa Rosa 6300, La Pampa, Argentina
| | - Maria Ines Vaccaro
- Institute of Biochemistry and Molecular Medicine (UBA-CONICET), Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires C1113AAD, Argentina
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Silva Z, Ferro T, Almeida D, Soares H, Ferreira JA, Deschepper FM, Hensbergen PJ, Pirro M, van Vliet SJ, Springer S, Videira PA. MHC Class I Stability is Modulated by Cell Surface Sialylation in Human Dendritic Cells. Pharmaceutics 2020; 12:pharmaceutics12030249. [PMID: 32164343 PMCID: PMC7150992 DOI: 10.3390/pharmaceutics12030249] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/04/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023] Open
Abstract
Maturation of human Dendritic Cells (DCs) is characterized by increased expression of antigen presentation molecules, and overall decreased levels of sialic acid at cell surface. Here, we aimed to identify sialylated proteins at DC surface and comprehend their role and modulation. Mass spectrometry analysis of DC’s proteins, pulled down by a sialic acid binding lectin, identified molecules of the major human histocompatibility complex class I (MHC-I), known as human leucocyte antigen (HLA). After desialylation, DCs showed significantly higher reactivity with antibodies specific for properly folded MHC-I-β2-microglobulin complex and for β2-microglobulin but showed significant lower reactivity with an antibody specific for free MHC-I heavy chain. Similar results for antibody reactivities were observed for TAP2-deficient lymphoblastoid T2 cells, which express HLA-A*02:01. Using fluorescent peptide specifically fitting the groove of HLA-A*02:01, instead of antibody staining, also showed higher peptide binding on desialylated cells, confirming higher surface expression of MHC-I complex. A decay assay showed that desialylation doubled the half-life of MHC-I molecules at cell surface in both DCs and T2 cells. The biological impact of DC´s desialylation was evaluated in co-cultures with autologous T cells, showing higher number and earlier immunological synapses, and consequent significantly increased production of IFN-γ by T cells. In summary, sialic acid content modulates the expression and stability of complex MHC-I, which may account for the improved DC-T synapses.
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Affiliation(s)
- Zélia Silva
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (Z.S.); (T.F.); (D.A.); (F.M.D.)
| | - Tiago Ferro
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (Z.S.); (T.F.); (D.A.); (F.M.D.)
- CDG & Allies – PPAIN- Congenital Disorders of Glycosylation & Allies - Professionals and Patient Associations International Network, 2829-516 Caparica, Portugal
| | - Danielle Almeida
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (Z.S.); (T.F.); (D.A.); (F.M.D.)
| | - Helena Soares
- Human Immunobiology and Pathogenesis, CEDOC-Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1150-082 Lisbon, Portugal;
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal;
- Porto Comprehensive Cancer Center (P.ccc), 4200-072 Porto, Portugal
| | - Fanny M. Deschepper
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (Z.S.); (T.F.); (D.A.); (F.M.D.)
| | - Paul J. Hensbergen
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (P.J.H.); (M.P.)
| | - Martina Pirro
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (P.J.H.); (M.P.)
| | - Sandra J. van Vliet
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, De Boelelaan 1117, 1081 HzAmsterdam, The Netherlands;
| | - Sebastian Springer
- Department of Life Sciences and Chemistry, Jacobs University, 28759 Bremen, Germany;
| | - Paula A. Videira
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal; (Z.S.); (T.F.); (D.A.); (F.M.D.)
- CDG & Allies – PPAIN- Congenital Disorders of Glycosylation & Allies - Professionals and Patient Associations International Network, 2829-516 Caparica, Portugal
- Correspondence: ; Tel.: +351-212948530
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Gupta R, Leon F, Rauth S, Batra SK, Ponnusamy MP. A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis. Cells 2020; 9:E446. [PMID: 32075174 PMCID: PMC7072808 DOI: 10.3390/cells9020446] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/10/2020] [Accepted: 02/12/2020] [Indexed: 12/27/2022] Open
Abstract
Glycosylation is the most commonly occurring post-translational modifications, and is believed to modify over 50% of all proteins. The process of glycan modification is directed by different glycosyltransferases, depending on the cell in which it is expressed. These small carbohydrate molecules consist of multiple glycan families that facilitate cell-cell interactions, protein interactions, and downstream signaling. An alteration of several types of O-glycan core structures have been implicated in multiple cancers, largely due to differential glycosyltransferase expression or activity. Consequently, aberrant O-linked glycosylation has been extensively demonstrated to affect biological function and protein integrity that directly result in cancer growth and progression of several diseases. Herein, we provide a comprehensive review of several initiating enzymes involved in the synthesis of O-linked glycosylation that significantly contribute to a number of different cancers.
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Affiliation(s)
- Rohitesh Gupta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA; (R.G.); (F.L.); (S.R.)
| | - Frank Leon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA; (R.G.); (F.L.); (S.R.)
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA; (R.G.); (F.L.); (S.R.)
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA; (R.G.); (F.L.); (S.R.)
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 681980-5900, USA
- Department of Pathology and Microbiology, UNMC, Omaha, NE 68198-5900, USA
| | - Moorthy P. Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA; (R.G.); (F.L.); (S.R.)
- Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 681980-5900, USA
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Zhang G, Lu J, Yang M, Wang Y, Liu H, Xu C. Elevated GALNT10 expression identifies immunosuppressive microenvironment and dismal prognosis of patients with high grade serous ovarian cancer. Cancer Immunol Immunother 2020; 69:175-187. [PMID: 31853576 DOI: 10.1007/s00262-019-02454-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 12/09/2019] [Indexed: 01/07/2023]
Abstract
High grade ovarian serous cancer (HGSC) is a malignant disease with high mortality. Glycosylation plays important roles in tumor invasion and immune evasion, but its effect on the immune microenvironment of HGSC remains unclear. This study examined the association of glycosyltransferase expression with HGSC prognosis and explored the underlying mechanism using clinical specimens and integrated bioinformatic analyses. We identified a cluster of 15 glycogenes associated with reduced overall survival, and GALNT10 was found to be an independent predictor of HGSC prognosis. The high GALNT10 expression was associated with increased regulatory CD4+ T cells infiltration and decreased granzyme B expression in CD8+ T cells. The expression of GALNT10 and its product, Tn antigen, in HGSC specimens was associated with the increased infiltration of M2 macrophages and neutrophils, and the decreased infiltration of CD3+ T cells, NK cells, and B cells. Taken collectively, high GALNT10 expression confers with immunosuppressive microenvironment to promote tumor progression and predicts poor clinical outcomes in HGSC patients.
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Affiliation(s)
- Guodong Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, No. 128, Shenyang Road, Shanghai, 200011, China
| | - Jiaqi Lu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
- Department of Gynecology, Kashgar Prefecture Second People's Hospital, Kashi, Xinjiang, 844000, China
| | - Moran Yang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, China
| | - Yiying Wang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, China
| | - Haiou Liu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, China.
| | - Congjian Xu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, No. 128, Shenyang Road, Shanghai, 200011, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, China.
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Kvorjak M, Ahmed Y, Miller ML, Sriram R, Coronnello C, Hashash JG, Hartman DJ, Telmer CA, Miskov-Zivanov N, Finn OJ, Cascio S. Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer. Cancer Immunol Res 2019; 8:167-178. [PMID: 31831633 DOI: 10.1158/2326-6066.cir-19-0514] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/03/2019] [Accepted: 12/03/2019] [Indexed: 12/21/2022]
Abstract
Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage-associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC.See related Spotlight on p. 160.
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Affiliation(s)
- Michael Kvorjak
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yasmine Ahmed
- Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michelle L Miller
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Raahul Sriram
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Jana G Hashash
- Department of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Douglas J Hartman
- Department of Pathology University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Cheryl A Telmer
- Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania
| | - Natasa Miskov-Zivanov
- Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Olivera J Finn
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sandra Cascio
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. .,Fondazione Ri.Med, Palermo, Italy.,Department of Obstetrics, Gynecology, & Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
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Crispen PL, Kusmartsev S. Mechanisms of immune evasion in bladder cancer. Cancer Immunol Immunother 2019; 69:3-14. [PMID: 31811337 PMCID: PMC6949323 DOI: 10.1007/s00262-019-02443-4] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022]
Abstract
With the introduction of multiple new agents, the role of immunotherapy is rapidly expanding across all malignancies. Bladder cancer is known to be immunogenic and is responsive to immunotherapy including intravesical BCG and immune checkpoint inhibitors. Multiple trials have addressed the role of checkpoint inhibitors in advanced bladder cancer, including atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab (all targeting the PD1/PD-L1 pathway). While these trials have demonstrated promising results and improvements over existing therapies, less than half of patients with advanced disease demonstrate clinical benefit from checkpoint inhibitor therapy. Recent breakthroughs in cancer biology and immunology have led to an improved understanding of the influence of the tumor microenvironment on the host’s immune system. It appears that tumors promote the formation of highly immunosuppressive microenvironments preventing generation of effective anti-tumor immune response through multiple mechanisms. Therefore, reconditioning of the tumor microenvironment and restoration of the competent immune response is essential for achieving optimal efficacy of cancer immunotherapy. In this review, we aim to discuss the major mechanisms of immune evasion in bladder cancer and highlight novel pathways and molecular targets that may help to attenuate tumor-induced immune tolerance, overcome resistance to immunotherapy and improve clinical outcomes.
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Affiliation(s)
- Paul L Crispen
- Department of Urology, University of Florida, College of Medicine, 1200 Newell Dr, PO BOX 100247, Gainesville, FL, 32610, USA
| | - Sergei Kusmartsev
- Department of Urology, University of Florida, College of Medicine, 1200 Newell Dr, PO BOX 100247, Gainesville, FL, 32610, USA.
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Seranio N, Malkowicz SB, Christodouleas J, Kao GD. Molecular/ Genetic/ Protein Characterizing of Bladder Cancer Circulating Tumor Cells. Bladder Cancer 2019. [DOI: 10.3233/blc-190227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Nicolas Seranio
- Department of Urology (presently resident physician, Stanford Department of Urology), University of Pennsylvania School of Medicine, Pennsylvania, PA, USA
| | - S. Bruce Malkowicz
- Department of Urology, University of Pennsylvania School of Medicine, Pennsylvania, PA, USA
| | - John Christodouleas
- Department of Radiation Oncology, University of Pennsylvania School of Medicine, Pennsylvania, PA, USA
| | - Gary D. Kao
- Department of Radiation Oncology, University of Pennsylvania School of Medicine, Pennsylvania, PA, USA
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Joseph M, Enting D. Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications. Front Oncol 2019; 9:1270. [PMID: 31824850 PMCID: PMC6879653 DOI: 10.3389/fonc.2019.01270] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Accepted: 11/04/2019] [Indexed: 12/21/2022] Open
Abstract
Immunosurveillance, which describes the immunologically mediated elimination of transformed cells, has been widely accepted in the context of bladder cancer for many decades with the successful use of Bacillus-Calmette Guerin for superficial bladder cancer since the 1970s. With the emergence of checkpoint inhibitor blockade in the treatment of urothelial cancers, there has been a resurgent interest in the immunology of bladder cancer. The theory of cancer immunoediting proposes that the immune system has both pro-tumorigenic and anti-tumor effects, the balance between the two determining the progression of an individual tumor. However, whilst there is evidence for the action of various immune cell populations in bladder cancer, a cohesive picture of the immune response to bladder cancer and its driving forces are still lacking. Additionally, little is still known about the normal immune landscape of the bladder. Future progress in bladder cancer therapeutic approaches will require a strong foundation in understanding the immunology of this disease. This review considers the evidence for the role of the main immune cell populations, both innate and adaptive, in the immune response to bladder cancer. Recent research and overarching themes in the immune response to bladder cancer are explored. The minimal evidence regarding the normal immune landscape of the human bladder is also summarized to contextualize downstream immune responses. Of specific interest are the innate and myeloid populations, some of which are resident in the human bladder and which have significant effects on downstream adaptive tumor immunity. We discuss factors which restrain the efficacy of populations known to have anti-tumor activity such as cytotoxic T cells, including the constraints on checkpoint blockade. Additionally, the effects on the immune response of tumor intrinsic factors such as the genomic subtype of bladder cancer and the effect of common therapies such as chemotherapy and intravesical Bacillus Calmette-Guerin are considered. A significant theme is the polarization of immune responses within the tumor by a heavily immunosuppressive tumor microenvironment which affects the phenotype of multiple innate and adaptive populations. Throughout, clinical implications are discussed with suggestions for future research directions and therapeutic targeting.
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Affiliation(s)
- Magdalene Joseph
- Hayday Laboratory, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Deborah Enting
- Department of Uro-Oncology, Guy's Hospital, Guy's St Thomas NHS Foundation Trust, London, United Kingdom
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Thomas D, Sagar S, Caffrey T, Grandgenett PM, Radhakrishnan P. Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells. J Cell Mol Med 2019; 23:6885-6896. [PMID: 31389667 PMCID: PMC6787448 DOI: 10.1111/jcmm.14572] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/23/2019] [Accepted: 07/09/2019] [Indexed: 12/11/2022] Open
Abstract
Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.
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Affiliation(s)
- Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNEUSA
| | - Satish Sagar
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNEUSA
| | - Thomas Caffrey
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNEUSA
| | - Paul M. Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNEUSA
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNEUSA
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Ferreira IG, Carrascal M, Mineiro AG, Bugalho A, Borralho P, Silva Z, Dall'olio F, Videira PA. Carcinoembryonic antigen is a sialyl Lewis x/a carrier and an E‑selectin ligand in non‑small cell lung cancer. Int J Oncol 2019; 55:1033-1048. [PMID: 31793656 PMCID: PMC6776192 DOI: 10.3892/ijo.2019.4886] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 08/28/2019] [Indexed: 12/24/2022] Open
Abstract
The formation of distant metastasis resulting from vascular dissemination is one of the leading causes of mortality in non-small cell lung cancer (NSCLC). This metastatic dissemination initiates with the adhesion of circulating cancer cells to the endothelium. The minimal requirement for the binding of leukocytes to endothelial E-selectins and subsequent transmigration is the epitope of the fucosylated glycan, sialyl Lewis x (sLex), attached to specific cell surface glycoproteins. sLex and its isomer sialyl Lewis a (sLea) have been described in NSCLC, but their functional role in cancer cell adhesion to endothelium is still poorly understood. In this study, it was hypothesised that, similarly to leukocytes, sLe glycans play a role in NSCLC cell adhesion to E-selectins. To assess this, paired tumour and normal lung tissue samples from 18 NSCLC patients were analyzed. Immunoblotting and immunohisto-chemistry assays demonstrated that tumour tissues exhibited significantly stronger reactivity with anti-sLex/sLea antibody and E-selectin chimera than normal tissues (2.2- and 1.8-fold higher, respectively), as well as a higher immunoreactive score. High sLex/sLea expression was associated with bone metastasis. The overall α1,3-fucosyltransferase (FUT) activity was increased in tumour tissues, along with the mRNA levels of FUT3, FUT6 and FUT7, whereas FUT4 mRNA expression was decreased. The expression of E-selectin ligands exhibited a weak but significant correlation with the FUT3/FUT4 and FUT7/FUT4 ratios. Additionally, carcinoembryonic antigen (CEA) was identified in only 8 of the 18 tumour tissues; CEA-positive tissues exhibited significantly increased sLex/sLea expression. Tumour tissue areas expressing CEA also expressed sLex/sLea and showed reactivity to E-selectin. Blot rolling assays further demonstrated that CEA immunoprecipitates exhibited sustained adhesive interactions with E-selectin-expressing cells, suggesting CEA acts as a functional protein scaffold for E-selectin ligands in NSCLC. In conclusion, this work provides the first demonstration that sLex/sLea are increased in primary NSCLC due to increased α1,3-FUT activity. sLex/sLea is carried by CEA and confers the ability for NSCLC cells to bind E-selectins, and is potentially associated with bone metastasis. This study contributes to identifying potential future diagnostic/prognostic biomarkers and therapeutic targets for lung cancer.
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Affiliation(s)
- Inês Gomes Ferreira
- Department of Experimental Diagnostic and Specialty Medicine, University of Bologna, Bologna I‑40126, Italy
| | - Mylène Carrascal
- CEDOC, NOVA Medical School, NOVA University of Lisbon, Lisbon 1150‑082, Portugal
| | - A Gonçalo Mineiro
- UCIBIO, Department of Life Sciences, Faculty of Sciences and Technology, NOVA University of Lisbon, Caparica 2829‑516, Portugal
| | - António Bugalho
- CEDOC, NOVA Medical School, NOVA University of Lisbon, Lisbon 1150‑082, Portugal
| | - Paula Borralho
- Department of Anatomical Pathology, Faculty of Medicine, University of Lisbon, Lisbon 1649‑028, Portugal
| | - Zélia Silva
- UCIBIO, Department of Life Sciences, Faculty of Sciences and Technology, NOVA University of Lisbon, Caparica 2829‑516, Portugal
| | - Fabio Dall'olio
- Department of Experimental Diagnostic and Specialty Medicine, University of Bologna, Bologna I‑40126, Italy
| | - Paula A Videira
- CEDOC, NOVA Medical School, NOVA University of Lisbon, Lisbon 1150‑082, Portugal
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48
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Casal D, Iria I, Ramalho JS, Alves S, Mota-Silva E, Mascarenhas-Lemos L, Pontinha C, Guadalupe-Cabral M, Ferreira-Silva J, Ferraz-Oliveira M, Vassilenko V, Goyri-O'Neill J, Pais D, Videira PA. BD-2 and BD-3 increase skin flap survival in a model of ischemia and Pseudomonas aeruginosa infection. Sci Rep 2019; 9:7854. [PMID: 31133641 PMCID: PMC6536547 DOI: 10.1038/s41598-019-44153-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 05/09/2019] [Indexed: 02/08/2023] Open
Abstract
The main aim of this work was to study the usefulness of human β-defensins 2 (BD-2) and 3 (BD-3), which are part of the innate immune system, in the treatment of infected ischemic skin flaps. We investigated the effect of transducing rat ischemic skin flaps with lentiviral vectors encoding human BD-2, BD-3, or both BD-2 and BD-3, to increase flap survival in the context of a P. aeruginosa infection associated with a foreign body. The secondary endpoints assessed were: bacterial counts, and biofilm formation on the surface of the foreign body. A local ischemic environment was created by producing arterialized venous flaps in the left epigastric region of rats. Flaps were intentionally infected by placing underneath them two catheters with 105 CFU of P. aeruginosa before the surgical wounds were hermetically closed. Flap biopsies were performed 3 and 7 days post-operatively, and the specimens submitted to immunohistochemical analysis for BD-2 and BD-3, as well as to bacterial quantification. Subsequently, the catheter segments were analyzed with scanning electron microscopy (SEM). Flaps transduced with BD-2 and BD-3 showed expression of these defensins and presented increased flap survival. Rats transduced with BD-3 presented a net reduction in the number of P. aeruginosa on the surface of the foreign body and lesser biofilm formation.
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Affiliation(s)
- Diogo Casal
- Anatomy Department, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal.
- Plastic and Reconstructive Surgery Department and Burn Unit, Centro Hospitalar de Lisboa Central - Hospital de São José, Lisbon, Portugal.
- UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisbon, Caparica, Portugal.
- CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
| | - Inês Iria
- UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisbon, Caparica, Portugal
- CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
- Molecular Microbiology and Biotechnology Unit, iMed, ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- INESC MN - Microsystems and Nanotechnologies, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - José S Ramalho
- CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Sara Alves
- Pathology Department, Centro Hospitalar de Lisboa Central - Hospital de São José, Lisbon, Portugal
| | - Eduarda Mota-Silva
- LIBPhys, Physics Department, Faculdade de Ciências e Tecnologias, Universidade NOVA de Lisboa, Lisbon, Caparica, Portugal
| | - Luís Mascarenhas-Lemos
- Anatomy Department, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
- Pathology Department, Centro Hospitalar de Lisboa Central - Hospital de São José, Lisbon, Portugal
| | - Carlos Pontinha
- Anatomy Department, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
- Pathology Department, Centro Hospitalar de Lisboa Central - Hospital de São José, Lisbon, Portugal
| | - Maria Guadalupe-Cabral
- CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - José Ferreira-Silva
- Pathology Department, Centro Hospitalar de Lisboa Central - Hospital de São José, Lisbon, Portugal
| | - Mário Ferraz-Oliveira
- Pathology Department, Centro Hospitalar de Lisboa Central - Hospital de São José, Lisbon, Portugal
| | - Valentina Vassilenko
- LIBPhys, Physics Department, Faculdade de Ciências e Tecnologias, Universidade NOVA de Lisboa, Lisbon, Caparica, Portugal
| | - João Goyri-O'Neill
- Anatomy Department, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Diogo Pais
- Anatomy Department, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Paula A Videira
- UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisbon, Caparica, Portugal.
- CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
- CDG & Allies- Professional and Patient Association International Network (PPAIN), Lisbon, Caparica, Portugal.
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49
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Itano N. Implications of altered O-glycosylation in tumour immune evasion. J Biochem 2019; 165:387-390. [PMID: 30649348 DOI: 10.1093/jb/mvz003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/10/2019] [Indexed: 01/08/2023] Open
Abstract
Aberrant glycosylation on tumour cells has been implicated in tumour immune modulation. A recent article published in The Journal of Biochemistry (Sutoh Yoneyama et al., A mechanism for evasion of CTL immunity by altered O-glycosylation of HLA class I, J. Biochem. 2017;161:479-492) showed that bladder cancer cells evaded cytotoxic T lymphocyte-mediated antitumour immunity by a novel mechanism involving the loss of Core 2 structures on human leukocyte antigen Class I O-glycans and subsequent impairment of galectin-glycan lattice formation. The immunosuppressive action of O-glycans on natural killer cell-mediated tumour immunity is also considered an immune evasion system. Furthermore, sialylated O-glycans have been proposed to play a central role in tumour immune escape by modulating the production of immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. Therefore, a better understanding of how alterations in O-glycosylation influence tumour immune evasion will enable the development of novel and more effective therapeutic options for cancer treatment.
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Affiliation(s)
- Naoki Itano
- Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto, Japan
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50
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Peixoto A, Relvas-Santos M, Azevedo R, Santos LL, Ferreira JA. Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks. Front Oncol 2019; 9:380. [PMID: 31157165 PMCID: PMC6530332 DOI: 10.3389/fonc.2019.00380] [Citation(s) in RCA: 219] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
Decades of research have disclosed a plethora of alterations in protein glycosylation that decisively impact in all stages of disease and ultimately contribute to more aggressive cell phenotypes. The biosynthesis of cancer-associated glycans and its reflection in the glycoproteome is driven by microenvironmental cues and these events act synergistically toward disease evolution. Such intricate crosstalk provides the molecular foundations for the activation of relevant oncogenic pathways and leads to functional alterations driving invasion and disease dissemination. However, it also provides an important source of relevant glyco(neo)epitopes holding tremendous potential for clinical intervention. Therefore, we highlight the transversal nature of glycans throughout the currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the tumor microenvironment stromal components. Focus is also set on the pressing need to include glycans and glycoconjugates in comprehensive panomics models envisaging molecular-based precision medicine capable of improving patient care. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention.
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Affiliation(s)
- Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.,Tumour and Microenvironment Interactions Group, INEB-Institute for Biomedical Engineering, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Marta Relvas-Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal
| | - Rita Azevedo
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.,Porto Comprehensive Cancer Center, Porto, Portugal
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