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Teng C, Ma W, Liu J, Hou J, Zhang Y, Meng X, Xue Y, Wang Z, Wang J, Chen D, Sui Q, Gao Q, Li X, Li T, Zong C. Chemoenzymatic liquid-phase synthesis and immunogenic assessment of tumor-associated complex MUC1 glycopeptide variants. Int J Biol Macromol 2025; 302:140525. [PMID: 39892541 DOI: 10.1016/j.ijbiomac.2025.140525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/15/2025] [Accepted: 01/29/2025] [Indexed: 02/03/2025]
Abstract
Aberrantly glycosylated Mucin 1 (MUC1) is frequently over-expressed in epithelial cancers, making it an attractive target for cancer vaccines. Over the past two decades, multiple MUC1-based vaccines have been investigated clinically, yet they have generally shown limited efficacy due to challenges such as low immunogenicity, difficulty in overcoming immune tolerance, and potential issues related to glycosylation effects and antigen presentations. To advance the understanding of MUC1 vaccines, we report an efficient chemo-enzymatic approach for the preparation of four MUC1 antigen variants with different glycoforms through liquid-phase glycopeptide synthesis. These antigen were conjugated with CRM197 to generate various glycopeptide-protein conjugate vaccines, and their immunogenicity was evaluated based on total and subtype antibody titers, binding affinity, complement-dependent cytotoxicity (CDC) activity, and antibody-dependent cellular phagocytosis (ADCP). The combination of MPL and QS21 adjuvants with STn-MUC1-CRM197 conjugate induced a potent Th1-biased immune response, evidenced by elevating IgG2a titers and stronger antibody binding to MCF-7 cells. This formulation demonstrated superior CDC activity, ADCP activity and binding affinity to human breast cancer tissues in immuno-histochemical assays. The synergistic effect of specific adjuvants and glycosylated MUC1 conjugates offers a strategic avenue for MUC1 cancer vaccine development.
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Affiliation(s)
- Changcai Teng
- School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China
| | - Wenjing Ma
- State Key Laboratory of Chemical Biology, Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jinfeng Liu
- State Key Laboratory of Chemical Biology, Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; Joint National Laboratory for Antibody Drug Engineering, School of Medicine, Henan University, Kaifeng 475004, China
| | - Juan Hou
- Clinical Laboratory, Binzhou Medical University Hospital, Binzhou 256600, China
| | - Yalong Zhang
- Department of Pathology, Binzhou Medical University Hospital, Binzhou 256600, China
| | - Xiongyan Meng
- School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China
| | - Yannan Xue
- School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China
| | - Zhen Wang
- School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China
| | - Jiajia Wang
- Joint National Laboratory for Antibody Drug Engineering, School of Medicine, Henan University, Kaifeng 475004, China
| | - Dexiang Chen
- Maxvax Biotechnology Co., LTD, Chengdu 610200, China
| | - Qiang Sui
- Maxvax Biotechnology Co., LTD, Chengdu 610200, China
| | - Qi Gao
- Maxvax Biotechnology Co., LTD, Chengdu 610200, China
| | - Xia Li
- Joint National Laboratory for Antibody Drug Engineering, School of Medicine, Henan University, Kaifeng 475004, China.
| | - Tiehai Li
- State Key Laboratory of Chemical Biology, Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Chengli Zong
- School of Pharmaceutical Sciences, Key Laboratory of Tropical Biological Resources of Ministry of Education, Hainan University, Haikou 570228, China.
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Dieli R, Lioy R, Crispo F, Cascelli N, Martinelli M, Lerose R, Telesca D, Milella MR, Colella M, Loperte S, Mazzoccoli C. The Oncoprotein Mucin 1 in Pancreatic Cancer Onset and Progression: Potential Clinical Implications. Biomolecules 2025; 15:275. [PMID: 40001578 PMCID: PMC11853026 DOI: 10.3390/biom15020275] [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: 12/11/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by poor prognosis, therapeutic resistance, and frequent recurrence. Current therapeutic options for PDAC include surgery, radiotherapy, immunological and targeted approaches. However, all these therapies provide only a slight improvement in patient survival. Consequently, the discovery of novel specific targets is becoming a priority to develop more effective treatments for PDAC. Mucin 1 (MUC1), a transmembrane glycoprotein, is aberrantly glycosylated and frequently overexpressed in pancreatic cancer. Recent studies highlighted the role of this oncoprotein in pancreatic carcinogenesis and its involvement in the acquisition of typical aggressive features of PDAC, like local invasion, metastases, and drug resistance. This review explores the mechanisms by which MUC1 contributes to cancer onset and progression, with a focus on its potential role as a biomarker and novel therapeutic target for pancreatic adenocarcinoma treatment.
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Affiliation(s)
- Rosalia Dieli
- Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.D.); (R.L.); (N.C.); (M.M.); (C.M.)
| | - Rosa Lioy
- Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.D.); (R.L.); (N.C.); (M.M.); (C.M.)
| | - Fabiana Crispo
- Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.D.); (R.L.); (N.C.); (M.M.); (C.M.)
| | - Nicoletta Cascelli
- Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.D.); (R.L.); (N.C.); (M.M.); (C.M.)
| | - Mara Martinelli
- Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.D.); (R.L.); (N.C.); (M.M.); (C.M.)
| | - Rosa Lerose
- Hospital Pharmacy, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.L.); (D.T.); (M.R.M.)
| | - Donatella Telesca
- Hospital Pharmacy, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.L.); (D.T.); (M.R.M.)
| | - Maria Rita Milella
- Hospital Pharmacy, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.L.); (D.T.); (M.R.M.)
| | - Marco Colella
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Simona Loperte
- Institute of Methodologies for Environmental Analysis, National Research Council, 85050 Tito Scalo, Italy;
| | - Carmela Mazzoccoli
- Laboratory of Pre-Clinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (R.D.); (R.L.); (N.C.); (M.M.); (C.M.)
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McMillan MT, Soares KC. Advances in Vaccine-Based Therapies for Pancreatic Cancer. J Gastrointest Cancer 2025; 56:62. [PMID: 39939414 PMCID: PMC11821674 DOI: 10.1007/s12029-025-01165-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2025] [Indexed: 02/14/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a 5-year survival rate that has improved only marginally over the past 30 years, despite numerous clinical trials. PDAC poses several unique challenges, including early metastatic spread and a predilection for liver metastasis. It is also highly resistant to anti-tumor immunity and immunotherapy due to its dense and immunosuppressive tumor microenvironment, low immunogenicity, and systemic immune suppression. PDAC has a low mutational burden, defective antigen presentation, and immune checkpoint molecule upregulation, which reduce immune recognition. Together, these factors leave PDAC as an "immune cold" tumor with minimal cytotoxic T-cell activity. Novel therapeutic approaches are urgently needed to reinvigorate anti-tumor immunity. Recent advances, such as adjuvant personalized mRNA neoantigen vaccines and mutant-KRAS targeted vaccines, have demonstrated sustained vaccine-induced T cell responses that are associated with improved recurrence-free survival in surgically resected PDAC. Combining different vaccine approaches with optimal sequencing of chemotherapy, surgery, radiotherapy, and other immunotherapies may further enhance outcomes. PDAC vaccines represent a promising strategy for overcoming PDAC's resistance to conventional therapies, with ongoing trials exploring their potential to improve long-term survival.
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Affiliation(s)
- Matthew T McMillan
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School, 1275 York Ave, C887, New York, NY, 10065, USA
| | - Kevin C Soares
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School, 1275 York Ave, C887, New York, NY, 10065, USA.
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Graciotti M, Kandalaft LE. Vaccines for cancer prevention: exploring opportunities and navigating challenges. Nat Rev Drug Discov 2025; 24:134-150. [PMID: 39622986 DOI: 10.1038/s41573-024-01081-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 02/06/2025]
Abstract
Improved understanding of cancer immunology has gradually brought increasing attention towards cancer-preventive vaccines as an important tool in the fight against cancer. The aim of this approach is to reduce cancer occurrence by inducing a specific immune response targeting tumours at an early stage before they can fully develop. The great advantage of preventive cancer vaccines lies in the potential to harness a less-compromised immune system in vaccine recipients before their immune responses become affected by the advanced status of the disease itself or by aggressive treatments such as chemotherapy. Successful implementation of immunoprevention against oncogenic viruses such as hepatitis B and papillomavirus has led to a dramatic decrease in virally induced cancers. Extending this approach to other cancers holds great promise but remains a major challenge. Here, we provide a comprehensive review of preclinical evidence supporting this approach, encouraging results from pioneering clinical studies as well as a discussion on the key aspects and open questions to address in order to design potent prophylactic cancer vaccines in the near future.
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Affiliation(s)
- Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Lana E Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
- Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland.
- AGORA Cancer Research Center, Lausanne, Lausanne, Switzerland.
- Swiss Medical Network, Genolier Innovation Network, Genolier Clinic, Genolier, Switzerland.
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Cameron CM, Raghu V, Richardson B, Zagore LL, Tamilselvan B, Golden J, Cartwright M, Schoen RE, Finn OJ, Benos PV, Cameron MJ. Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention. Front Immunol 2024; 15:1437391. [PMID: 39450169 PMCID: PMC11499122 DOI: 10.3389/fimmu.2024.1437391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Introduction Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Methods Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. Results MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. Discussion These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.
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Affiliation(s)
- Cheryl M. Cameron
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
| | - Vineet Raghu
- Department of Computer Science, University of Pittsburgh, Pittsburgh, PA, United States
- Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States
| | - Brian Richardson
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Leah L. Zagore
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Banumathi Tamilselvan
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
| | - Jackelyn Golden
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Michael Cartwright
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Robert E. Schoen
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States
| | - Olivera J. Finn
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Panayiotis V. Benos
- Department of Epidemiology, University of Florida, Gainesville, FL, United States
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Mark J. Cameron
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
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Wang J, Yang J, Narang A, He J, Wolfgang C, Li K, Zheng L. Consensus, debate, and prospective on pancreatic cancer treatments. J Hematol Oncol 2024; 17:92. [PMID: 39390609 PMCID: PMC11468220 DOI: 10.1186/s13045-024-01613-x] [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: 08/16/2024] [Accepted: 09/25/2024] [Indexed: 10/12/2024] Open
Abstract
Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.
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Affiliation(s)
- Junke Wang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jie Yang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Amol Narang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jin He
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Christopher Wolfgang
- Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY, USA
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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Yao Y, Fan D. Advances in MUC1 resistance to chemotherapy in pancreatic cancer. J Chemother 2024; 36:449-456. [PMID: 38006297 DOI: 10.1080/1120009x.2023.2282839] [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: 07/26/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 11/27/2023]
Abstract
The incidence of pancreatic cancer (PC), a highly fatal malignancy, is increasing every year. Chemotherapy is an important treatment for it in addition to surgery, yet most patients become resistant to chemotherapeutic agents within a few weeks of treatment initiation. MUC1 is a highly glycosylated transmembrane protein, and studies have shown that aberrantly glycosylated overexpression of MUC1 is involved in regulating the biology of chemoresistance in cancer cells. This article summarizes the mechanism of MUC1 in PC chemoresistance and reviews MUC1-based targeted therapies.
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Affiliation(s)
- Youhao Yao
- The Fifth Clinical Medical College of Shanxi Medical University, Shanxi, PR China
- Surgery Department, Shanxi Provincial People's Hospital, Taiyuan, PR China
| | - Daguang Fan
- Surgery Department, Shanxi Provincial People's Hospital, Taiyuan, PR China
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Phan T, Fan D, Melstrom LG. Developing Vaccines in Pancreatic Adenocarcinoma: Trials and Tribulations. Curr Oncol 2024; 31:4855-4884. [PMID: 39329989 PMCID: PMC11430674 DOI: 10.3390/curroncol31090361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic adenocarcinoma represents one of the most challenging malignancies to treat, with dismal survival rates despite advances in therapeutic modalities. Immunotherapy, particularly vaccines, has emerged as a promising strategy to harness the body's immune system in combating this aggressive cancer. This abstract reviews the trials and tribulations encountered in the development of vaccines targeting pancreatic adenocarcinoma. Key challenges include the immunosuppressive tumor microenvironment, the heterogeneity of tumor antigens, and a limited understanding of immune evasion mechanisms employed by pancreatic cancer cells. Various vaccine platforms, including peptide-based, dendritic cell-based, and viral vector-based vaccines, have been explored in preclinical and clinical settings. However, translating promising results from preclinical models to clinical efficacy has proven elusive. In recent years, mRNA vaccines have emerged as a promising immunotherapeutic strategy in the fight against various cancers, including pancreatic adenocarcinoma. We will discuss the potential applications, opportunities, and challenges associated with mRNA vaccines in pancreatic cancer treatment.
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Affiliation(s)
- Thuy Phan
- Department of Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Darrell Fan
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Laleh G. Melstrom
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA;
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Liu D, Liu L, Li X, Wang S, Wu G, Che X. Advancements and Challenges in Peptide-Based Cancer Vaccination: A Multidisciplinary Perspective. Vaccines (Basel) 2024; 12:950. [PMID: 39204073 PMCID: PMC11359700 DOI: 10.3390/vaccines12080950] [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: 06/28/2024] [Revised: 08/09/2024] [Accepted: 08/21/2024] [Indexed: 09/03/2024] Open
Abstract
With the continuous advancements in tumor immunotherapy, researchers are actively exploring new treatment methods. Peptide therapeutic cancer vaccines have garnered significant attention for their potential in improving patient outcomes. Despite its potential, only a single peptide-based cancer vaccine has been approved by the U.S. Food and Drug Administration (FDA). A comprehensive understanding of the underlying mechanisms and current development status is crucial for advancing these vaccines. This review provides an in-depth analysis of the production principles and therapeutic mechanisms of peptide-based cancer vaccines, highlights the commonly used peptide-based cancer vaccines, and examines the synergistic effects of combining these vaccines with immunotherapy, targeted therapy, radiotherapy, and chemotherapy. While some studies have yielded suboptimal results, the potential of combination therapies remains substantial. Additionally, we addressed the management and adverse events associated with peptide-based cancer vaccines, noting their relatively higher safety profile compared to traditional radiotherapy and chemotherapy. Lastly, we also discussed the roles of adjuvants and targeted delivery systems in enhancing vaccine efficacy. In conclusion, this review comprehensively outlines the current landscape of peptide-based cancer vaccination and underscores its potential as a pivotal immunotherapy approach.
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Affiliation(s)
- Dequan Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Lei Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Xinghan Li
- Department of Stomatology, General Hospital of Northern Theater Command, Shenyang 110016, China;
| | - Shijin Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; (D.L.); (L.L.); (S.W.)
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Brugiapaglia S, Bulfamante S, Curcio C, Arigoni M, Calogero R, Bonello L, Genuardi E, Spadi R, Satolli MA, Campra D, Giordano D, Cappello P, Cordero F, Novelli F. In pancreatic cancer patients, chemotherapy reshapes the gene expression profile and antigen receptor repertoire of T lymphocytes and enhances their effector response to tumor-associated antigens. Front Immunol 2024; 15:1427424. [PMID: 39176093 PMCID: PMC11339620 DOI: 10.3389/fimmu.2024.1427424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 07/15/2024] [Indexed: 08/24/2024] Open
Abstract
Introduction Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy. Methods Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT. Results CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature. Conclusion These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT.
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MESH Headings
- Humans
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/therapy
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Male
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/genetics
- Carcinoma, Pancreatic Ductal/therapy
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/drug therapy
- Female
- Transcriptome
- Aged
- Middle Aged
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Gene Expression Regulation, Neoplastic
- Gene Expression Profiling
- Phosphopyruvate Hydratase/genetics
- Phosphopyruvate Hydratase/immunology
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
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Affiliation(s)
- Silvia Brugiapaglia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
| | - Maddalena Arigoni
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Raffaele Calogero
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Lisa Bonello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Elisa Genuardi
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Rosella Spadi
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Maria Antonietta Satolli
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Donata Campra
- Struttura Complessa (SC) Chirurgia generale d’urgenza e pronto soccorso, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Daniele Giordano
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
| | | | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center “Guido Tarone”, University of Turin, Turin, Italy
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11
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Yuan DY, McKeague ML, Raghu VK, Schoen RE, Finn OJ, Benos PV. Cellular and transcriptional profiles of peripheral blood mononuclear cells pre-vaccination predict immune response to preventative MUC1 vaccine. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.14.598031. [PMID: 38948837 PMCID: PMC11212910 DOI: 10.1101/2024.06.14.598031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial ( NCT02134925 ) were conducted in individuals with a history of advanced colonic adenoma to test the safety and immunogenicity of the MUC1 tumor antigen vaccine and its potential to prevent new adenomas. These were the first two trials of a non-viral cancer vaccine administered in the absence of cancer. The vaccine was safe and strongly immunogenic in 43% (NCT007773097) and 25% ( NCT02134925 ) of participants. The lack of response in a significant number of participants suggested, for the first time, that even in a premalignant setting, the immune system may have already been exposed to some level of suppression previously reported only in cancer. Single-cell RNA-sequencing (scRNA-seq) on banked pre-vaccination peripheral blood mononuclear cells (PBMCs) from 16 immune responders and 16 non-responders identified specific cell types, genes, and pathways of a productive vaccine response. Responders had a significantly higher percentage of CD4+ naive T cells pre-vaccination, but a significantly lower percentage of CD8+ T effector memory (TEM) cells and CD16+ monocytes. Differential gene expression (DGE) and transcription factor inference analysis showed a higher level of expression of T cell activation genes, such as Fos and Jun, in CD4+ naive T cells, and pathway analysis showed enriched signaling activity in responders. Furthermore, Bayesian network analysis suggested that these genes were mechanistically connected to response. Our analyses identified several immune mechanisms and candidate biomarkers to be further validated as predictors of immune responses to a preventative cancer vaccine that could facilitate selection of individuals likely to benefit from a vaccine or be used to improve vaccine responses.
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12
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Cameron CM, Raghu V, Richardson B, Zagore LL, Tamilselvan B, Golden J, Cartwright M, Schoen RE, Finn OJ, Benos PV, Cameron MJ. Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.09.24305336. [PMID: 38766010 PMCID: PMC11100921 DOI: 10.1101/2024.05.09.24305336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-kB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.
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Affiliation(s)
- Cheryl M Cameron
- Department of Nutrition, Case Western Reserve University, Cleveland, OH
| | - Vineet Raghu
- Department of Computer Science, University of Pittsburgh, Pittsburgh, PA
- Massachusetts General Hospital, Harvard Medical School, Cambridge, MA
| | - Brian Richardson
- Department of Nutrition, Case Western Reserve University, Cleveland, OH
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | - Leah L Zagore
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | | | - Jackelyn Golden
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | - Michael Cartwright
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | - Robert E Schoen
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA
| | - Olivera J Finn
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA
| | - Panayiotis V Benos
- Department of Epidemiology, University of Florida, Gainesville, FL
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA
| | - Mark J Cameron
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
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13
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Zheng R, Liu X, Zhang Y, Liu Y, Wang Y, Guo S, Jin X, Zhang J, Guan Y, Liu Y. Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application. Front Immunol 2024; 15:1383978. [PMID: 38756774 PMCID: PMC11096556 DOI: 10.3389/fimmu.2024.1383978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Pancreatic cancer is a highly aggressive malignant tumor, that is becoming increasingly common in recent years. Despite advances in intensive treatment modalities including surgery, radiotherapy, biological therapy, and targeted therapy, the overall survival rate has not significantly improved in patients with pancreatic cancer. This may be attributed to the insidious onset, unknown pathophysiology, and poor prognosis of the disease. It is therefore essential to identify and develop more effective and safer treatments for pancreatic cancer. Tumor immunotherapy is the new and fourth pillar of anti-tumor therapy after surgery, radiotherapy, and chemotherapy. Significant progress has made in the use of immunotherapy for a wide variety of malignant tumors in recent years; a breakthrough has also been made in the treatment of pancreatic cancer. This review describes the advances in immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, oncolytic virus, and matrix-depletion therapies for the treatment of pancreatic cancer. At the same time, some new potential biomarkers and potential immunotherapy combinations for pancreatic cancer are discussed. The molecular mechanisms of various immunotherapies have also been elucidated, and their clinical applications have been highlighted. The current challenges associated with immunotherapy and proposed strategies that hold promise in overcoming these limitations have also been discussed, with the aim of offering new insights into immunotherapy for pancreatic cancer.
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Affiliation(s)
- Rui Zheng
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaobin Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yufu Zhang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China
| | - Yongxian Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yaping Wang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Shutong Guo
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Xiaoyan Jin
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Jing Zhang
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yuehong Guan
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
| | - Yusi Liu
- Department of Medical Immunology, Medical College of Yan’an University, Yanan, Shaanxi, China
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14
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Murakami H, Takahama S, Akita H, Kobayashi S, Masuta Y, Nagatsuka Y, Higashiguchi M, Tomokuni A, Yoshida K, Takahashi H, Doki Y, Eguchi H, Matsuura N, Yamamoto T. Circulating tumor-associated antigen-specific IFNγ +4-1BB + CD8 + T cells as peripheral biomarkers of treatment outcomes in patients with pancreatic cancer. Front Immunol 2024; 15:1363568. [PMID: 38550601 PMCID: PMC10972947 DOI: 10.3389/fimmu.2024.1363568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/22/2024] [Indexed: 04/02/2024] Open
Abstract
CD8+ T cells affect the outcomes of pancreatic ductal adenocarcinoma (PDAC). Using tissue samples at pre-treatment to monitor the immune response is challenging, while blood samples are beneficial in overcoming this limitation. In this study, we measured peripheral antigen-specific CD8+ T cell responses against four different tumor-associated antigens (TAAs) in PDAC using flow cytometry and investigated their relationships with clinical features. We analyzed the optimal timing within the treatment course for effective immune checkpoint inhibition in vitro. We demonstrated that the frequency of TAA-specific IFNγ+4-1BB+ CD8+ T cells was correlated with a fold reduction in CA19-9 before and after neoadjuvant therapy. Moreover, patients with TAA-specific IFNγ+4-1BB+ CD8+ T cells after surgery exhibited a significantly improved disease-free survival. Anti-PD-1 treatment in vitro increased the frequency of TAA-specific IFNγ+4-1BB+ CD8+ T cells before neoadjuvant therapy in patients, suggesting the importance of the timing of anti-PD-1 inhibition during the treatment regimen. Our results indicate that peripheral immunophenotyping, combined with highly sensitive identification of TAA-specific responses in vitro as well as detailed CD8+ T cell subset profiling via ex vivo analysis, may serve as peripheral biomarkers to predict treatment outcomes and therapeutic efficacy of immunotherapy plus neoadjuvant chemotherapy.
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Affiliation(s)
- Hirotomo Murakami
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shokichi Takahama
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Hirofumi Akita
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
- Next-Generation Precision Medicine Research Center, Osaka International Cancer Institute, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuji Masuta
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Yuta Nagatsuka
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masaya Higashiguchi
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Akira Tomokuni
- Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan
| | - Keiichi Yoshida
- Next-Generation Precision Medicine Research Center, Osaka International Cancer Institute, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Nariaki Matsuura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Takuya Yamamoto
- Laboratory of Precision Immunology, Center for Intractable Diseases and ImmunoGenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Next-Generation Precision Medicine Research Center, Osaka International Cancer Institute, Osaka, Japan
- Laboratory of Aging and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- Department of Virology and Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
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15
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Arabi A, Aria (Soltani) S, Maniaci B, Mann K, Martinson H, Kullberg M. Enhancing T Cell and Antibody Response in Mucin-1 Transgenic Mice through Co-Delivery of Tumor-Associated Mucin-1 Antigen and TLR Agonists in C3-Liposomes. Pharmaceutics 2023; 15:2774. [PMID: 38140114 PMCID: PMC10747059 DOI: 10.3390/pharmaceutics15122774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Mucin-1 (MUC1) is a highly relevant antigen for cancer vaccination due to its overexpression and hypo-glycosylation in a high percentage of carcinomas. To enhance the immune response to MUC1, our group has developed C3-liposomes that encapsulate the MUC1 antigen along with immunostimulatory compounds for direct delivery to antigen-presenting cells (APCs). C3-liposomes bind complement C3, which interacts with C3-receptors on APCs, resulting in liposomal uptake and the delivery of tumor antigens to APCs in a manner that mimics pathogenic uptake. In this study, MUC1 and Toll-like receptor (TLR) agonists were encapsulated in C3-liposomes to provoke an immune response in transgenic mice tolerant to MUC1. The immune response to the C3-bound MUC1 liposomal vaccine was assessed by ELISA, ELISpot, and flow cytometry. Co-administering TLR 7/8 agonists with MUC1 encapsulated in C3-liposomes resulted in a significant antibody response compared to non-encapsulated MUC1. This antibody response was significantly higher in females than in males. The co-encapsulation of three TLR agonists with MUC1 in C3-liposomes significantly increased antibody responses and eliminated sex-based differences. Furthermore, this immunization strategy resulted in a significantly increased T cell-response compared to other treatment groups. In conclusion, the co-delivery of MUC1 and TLR agonists via C3-liposomes greatly enhances the immune response to MUC1, highlighting its potential for antigen-specific cancer immunotherapy.
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Affiliation(s)
- Ameneh Arabi
- WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence, Anchorage, AK 99508, USA; (A.A.); (S.A.); (B.M.); (H.M.)
- Johns Hopkins Medicine, Johns Hopkins University, 1551 Jefferson St., Baltimore, MD 21287, USA
| | - Shahab Aria (Soltani)
- WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence, Anchorage, AK 99508, USA; (A.A.); (S.A.); (B.M.); (H.M.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, 503 Robert Grant Ave, Silver Spring, MD 20910, USA
| | - Brandon Maniaci
- WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence, Anchorage, AK 99508, USA; (A.A.); (S.A.); (B.M.); (H.M.)
- Department of Immunology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
| | - Kristine Mann
- Department of Biological Sciences, University of Alaska Anchorage, Anchorage, AK 99508, USA;
| | - Holly Martinson
- WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence, Anchorage, AK 99508, USA; (A.A.); (S.A.); (B.M.); (H.M.)
| | - Max Kullberg
- WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence, Anchorage, AK 99508, USA; (A.A.); (S.A.); (B.M.); (H.M.)
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16
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Leowattana W, Leowattana P, Leowattana T. Systemic treatment for advanced pancreatic cancer. World J Gastrointest Oncol 2023; 15:1691-1705. [PMID: 37969416 PMCID: PMC10631439 DOI: 10.4251/wjgo.v15.i10.1691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/24/2023] [Accepted: 09/22/2023] [Indexed: 10/10/2023] Open
Abstract
Pancreatic cancer is a deadly disease with an extremely poor 5-year survival rate due to treatment resistance and late-stage detection. Despite numerous years of research and pharmaceutical development, these figures have not changed. Treatment options for advanced pancreatic cancer are still limited. This illness is typically detected at a late stage, making curative surgical resection impossible. Chemotherapy is the most commonly utilized technique for treating advanced pancreatic cancer but has poor efficacy. Targeted therapy and immunotherapy have made significant progress in many other cancer types and have been proven to have extremely promising possibilities; these therapies also hold promise for pancreatic cancer. There is an urgent need for research into targeted treatment, immunotherapy, and cancer vaccines. In this review, we emphasize the foundational findings that have fueled the therapeutic strategy for advanced pancreatic cancer. We also address current advancements in targeted therapy, immunotherapy, and cancer vaccines, all of which continue to improve the clinical outcome of advanced pancreatic cancer. We believe that clinical translation of these novel treatments will improve the low survival rate of this deadly disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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17
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Jin W, Zhang M, Dong C, Huang L, Luo Q. The multifaceted role of MUC1 in tumor therapy resistance. Clin Exp Med 2023; 23:1441-1474. [PMID: 36564679 DOI: 10.1007/s10238-022-00978-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
Tumor therapeutic resistances are frequently linked to the recurrence and poor prognosis of cancers and have been a key bottleneck in clinical tumor treatment. Mucin1 (MUC1), a heterodimeric transmembrane glycoprotein, exhibits abnormally overexpression in a variety of human tumors and has been confirmed to be related to the formation of therapeutic resistance. In this review, the multifaceted roles of MUC1 in tumor therapy resistance are summarized from aspects of pan-cancer principles shared among therapies and individual mechanisms dependent on different therapies. Concretely, the common mechanisms of therapy resistance across cancers include interfering with gene expression, promoting genome instability, modifying tumor microenvironment, enhancing cancer heterogeneity and stemness, and activating evasion and metastasis. Moreover, the individual mechanisms of therapy resistance in chemotherapy, radiotherapy, and biotherapy are introduced. Last but not least, MUC1-involved therapy resistance in different types of cancers and MUC1-related clinical trials are summarized.
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Affiliation(s)
- Weiqiu Jin
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
- Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Mengwei Zhang
- Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Changzi Dong
- Department of Bioengineering, School of Engineering and Science, University of Pennsylvania, Philadelphia, 19104, USA
| | - Lei Huang
- Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Innovative Research Team of High-Level Local Universities in Shanghai, Shanghai, China.
| | - Qingquan Luo
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China.
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18
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Post-Translational Modifications in Tumor-Associated Antigens as a Platform for Novel Immuno-Oncology Therapies. Cancers (Basel) 2022; 15:cancers15010138. [PMID: 36612133 PMCID: PMC9817968 DOI: 10.3390/cancers15010138] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Post-translational modifications (PTMs) are generated by adding small chemical groups to amino acid residues after the translation of proteins. Many PTMs have been reported to correlate with tumor progression, growth, and survival by modifying the normal functions of the protein in tumor cells. PTMs can also elicit humoral and cellular immune responses, making them attractive targets for cancer immunotherapy. This review will discuss how the acetylation, citrullination, and phosphorylation of proteins expressed by tumor cells render the corresponding tumor-associated antigen more antigenic and affect the immune response in multiple cancers. In addition, the role of glycosylated protein mucins in anti-cancer immunotherapy will be considered. Mucin peptides in combination with stimulating adjuvants have, in fact, been utilized to produce anti-tumor antibodies and vaccines. Finally, we will also outline the results of the clinical trial exploiting glycosylated-MUC1 as a vaccine in different cancers. Overall, PTMs in TAAs could be considered in future therapies to result in lasting anti-tumor responses.
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19
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Das A, Deka D, Banerjee A, Radhakrishnan AK, Zhang H, Sun XF, Pathak S. A Concise Review on the Role of Natural and Synthetically Derived Peptides in Colorectal Cancer. Curr Top Med Chem 2022; 22:2571-2588. [PMID: 35578849 DOI: 10.2174/1568026622666220516105049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 03/29/2022] [Accepted: 04/06/2022] [Indexed: 01/20/2023]
Abstract
Colorectal cancer being the second leading cause of cancer-associated deaths has become a significant health concern around the globe. Though there are various cancer treatment approaches, many of them show adverse effects and some compromise the health of cancer patients. Hence, significant efforts are being made for the evolution of a novel biological therapeutic approach with better efficacy and minimal side effects. Current research suggests that the application of peptides in colorectal cancer therapeutics holds the possibility of the emergence of an anticancer reagent. The primary beneficial factors of peptides are their comparatively rapid and easy process of synthesis and the enormous potential for chemical alterations that can be evaluated for designing novel peptides and enhancing the delivery capacity of peptides. Peptides might be utilized as agents with cytotoxic activities or as a carrier of a specific drug or as cytotoxic agents that can efficiently target the tumor cells. Further, peptides can also be used as a tool for diagnostic purposes. The recent analysis aims at developing peptides that have the potential to efficiently target the tumor moieties without harming the nearby normal cells. Additionally, decreasing the adverse effects, and unfolding the other therapeutic properties of potential peptides, are also the subject matter of in-depth analysis. This review provides a concise summary of the function of both natural and synthetically derived peptides in colorectal cancer therapeutics that are recently being evaluated and their potent applications in the clinical field.
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Affiliation(s)
- Alakesh Das
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Dikshita Deka
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Arun Kumar Radhakrishnan
- Department of Pharmacology, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
| | - Hong Zhang
- School of Medicine, Department of Medical Sciences, Örebro University, Örebro, Sweden
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, India
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20
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Hong J, Guo G, Wu S, Lin S, Zhou Z, Chen S, Ye C, Li J, Lin W, Ye Y. Altered MUC1 epitope-specific CTLs: A potential target for immunotherapy of pancreatic cancer. J Leukoc Biol 2022; 112:1577-1590. [PMID: 36222123 DOI: 10.1002/jlb.5ma0922-749r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 08/26/2022] [Indexed: 01/04/2023] Open
Abstract
The efficacy of conventional treatments for pancreatic cancer remains unsatisfactory, and immunotherapy is an emerging option for adjuvant treatment of this highly deadly disorder. The tumor-associated antigen (TAA) MUC1 is expressed in a variety of human cancers and is overexpressed in more than 90% of pancreatic cancer, which makes it an attractive target for cancer immunotherapy. As a self-protein, MUC1 shows a low immunogenicity because of immune tolerance, and the most effective approach to breaking immune tolerance is alteration of the antigen structure. In this study, the altered MUC11068-1076Y1 epitope (YLQRDISEM) by modification of amino acid residues in sequences presented a higher immunogenicity and elicited more CTLs relative to the wild-type (WT) MUC11068-1076 epitope (ELQRDISEM). In addition, the altered MUC11068-1076Y1 epitope was found to cross-recognize pancreatic cancer cells expressing WT MUC1 peptides in an HLA-A0201-restricted manner and trigger stronger immune responses against pancreatic cancer via the perforin/granzyme apoptosis pathway. As a potential HLA-A0201-restricted CTL epitope, the altered MUC11068-1076Y1 epitope is considered as a promising target for immunotherapy of pancreatic cancer. Alteration of epitope residues may be feasible to solve the problem of the low immunogenicity of TAA and break immune tolerance to induce immune responses against human cancers.
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Affiliation(s)
- Jingwen Hong
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China
| | - Guoxiang Guo
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China
| | - Suxin Wu
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China
| | - Shengzhe Lin
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, NO. 29, Xinquan Road, Fuzhou, Fujian 350001, China
| | - Zhifeng Zhou
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China.,Fujian Key Laboratory of Translational Cancer Medicine, No. 420, Fuma Road, Jinan District, Fuzhou City, Fujian 350014, China
| | - Shuping Chen
- Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China.,Fujian Key Laboratory of Translational Cancer Medicine, No. 420, Fuma Road, Jinan District, Fuzhou City, Fujian 350014, China
| | - Chunmei Ye
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China
| | - Jieyu Li
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China.,Fujian Key Laboratory of Translational Cancer Medicine, No. 420, Fuma Road, Jinan District, Fuzhou City, Fujian 350014, China
| | - Wansong Lin
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China.,Fujian Key Laboratory of Translational Cancer Medicine, No. 420, Fuma Road, Jinan District, Fuzhou City, Fujian 350014, China
| | - Yunbin Ye
- School of Basic Medical Sciences, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian, 350122, China.,Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, No. 420, Fuma Road, Jinan District, Fuzhou, Fujian, 350014, China.,Fujian Key Laboratory of Translational Cancer Medicine, No. 420, Fuma Road, Jinan District, Fuzhou City, Fujian 350014, China
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21
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Mukherji R, Debnath D, Hartley ML, Noel MS. The Role of Immunotherapy in Pancreatic Cancer. Curr Oncol 2022; 29:6864-6892. [PMID: 36290818 PMCID: PMC9600738 DOI: 10.3390/curroncol29100541] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 01/13/2023] Open
Abstract
Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.
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Affiliation(s)
- Reetu Mukherji
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Dipanjan Debnath
- Department of Internal Medicine, Medstar Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA
| | - Marion L. Hartley
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - Marcus S. Noel
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown Lombardi Comprehensive Cancer Center, Division of Hematology and Oncology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
- Correspondence:
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22
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Ullman NA, Burchard PR, Dunne RF, Linehan DC. Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot. J Clin Oncol 2022; 40:2789-2805. [PMID: 35839445 PMCID: PMC9390820 DOI: 10.1200/jco.21.02616] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 04/08/2022] [Accepted: 05/18/2022] [Indexed: 12/12/2022] Open
Abstract
The rising incidence and persistent dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for new effective systemic therapies. Immunotherapy has shown significant benefits in solid organ tumors, but has thus far been disappointing in the treatment of PDAC. There have been several promising preclinical studies, but translation into the clinic has proved to be challenging. This is likely a result of PDAC's complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Here, we summarize the mechanisms of immunosuppression within the PDAC tumor microenvironment and provide an up-to-date review of completed and ongoing clinical trials using various immunotherapy strategies.
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23
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Bose D, Roy L, Chatterjee S. Peptide therapeutics in the management of metastatic cancers. RSC Adv 2022; 12:21353-21373. [PMID: 35975072 PMCID: PMC9345020 DOI: 10.1039/d2ra02062a] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/26/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer remains a leading health concern threatening lives of millions of patients worldwide. Peptide-based drugs provide a valuable alternative to chemotherapeutics as they are highly specific, cheap, less toxic and easier to synthesize compared to other drugs. In this review, we have discussed various modes in which peptides are being used to curb cancer. Our review highlights specially the various anti-metastatic peptide-based agents developed by targeting a plethora of cellular factors. Herein we have given a special focus on integrins as targets for peptide drugs, as these molecules play key roles in metastatic progression. The review also discusses use of peptides as anti-cancer vaccines and their efficiency as drug-delivery tools. We hope this work will give the reader a clear idea of the mechanisms of peptide-based anti-cancer therapeutics and encourage the development of superior drugs in the future.
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Affiliation(s)
- Debopriya Bose
- Department of Biophysics Bose Institute Unified Academic Campus EN 80, Sector V, Bidhan Nagar Kolkata 700091 WB India
| | - Laboni Roy
- Department of Biophysics Bose Institute Unified Academic Campus EN 80, Sector V, Bidhan Nagar Kolkata 700091 WB India
| | - Subhrangsu Chatterjee
- Department of Biophysics Bose Institute Unified Academic Campus EN 80, Sector V, Bidhan Nagar Kolkata 700091 WB India
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24
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Baleeiro RB, Bouwens CJ, Liu P, Di Gioia C, Dunmall LSC, Nagano A, Gangeswaran R, Chelala C, Kocher HM, Lemoine NR, Wang Y. MHC class II molecules on pancreatic cancer cells indicate a potential for neo-antigen-based immunotherapy. Oncoimmunology 2022; 11:2080329. [PMID: 35655709 PMCID: PMC9154752 DOI: 10.1080/2162402x.2022.2080329] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 11/05/2022] Open
Abstract
MHC class II expression is a hallmark of professional antigen-presenting cells and key to the induction of CD4+ T helper cells. We found that these molecules are ectopically expressed on tumor cells in a large proportion of patients with pancreatic ductal adenocarcinoma (PDAC) and on several PDAC cell lines. In contrast to the previous reports that tumoral expression of MHC-II in melanoma enabled tumor cells to evade immunosurveillance, the expression of MHC-II on PDAC cells neither protected cancer cells from Fas-mediated cell death nor caused T-cell suppression by engagement with its ligand LAG-3 on activated T-cells. In fact and surprisingly, the MHC-II/LAG-3 pathway contributed to CD4+ and CD8+ T-cell cytotoxicity toward MHC-II-positive PDAC cells. By combining bioinformatic tools and cell-based assays, we identified a number of immunogenic neo-antigens that can be presented by the patients' HLA class II alleles. Furthermore, CD4+ T-cells stimulated with neo-antigens were capable of recognizing and killing a human PDAC cell line expressing the mutated genes. To expand this approach to a larger number of PDAC patients, we show that co-treatment with IFN-γ and/or MEK/HDAC inhibitors induced tumoral MHC-II expression on MHC-II-negative tumors that are IFN-γ-resistant. Taken together, our data point to the possibility of harnessing MHC-II expression on PDAC cells for neo-antigen-based immunotherapy.
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Affiliation(s)
- Renato B. Baleeiro
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Christian J. Bouwens
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Peng Liu
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Carmela Di Gioia
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Louisa S. Chard Dunmall
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Ai Nagano
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Rathistevy Gangeswaran
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Claude Chelala
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Hemant M. Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Nicholas R. Lemoine
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
- Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySino-British, Zhengzhou, Henan, China
| | - Yaohe Wang
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
- Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversitySino-British, Zhengzhou, Henan, China
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25
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Abstract
Antibodies against autologous tumor-associated antigens have been demonstrated as being useful biomarkers for early cancer diagnosis and prognosis. They have several advantages such as long half-life (7-30 days depending on subtiter of Ig), inherent stability in patients' blood due to not being subjected to proteolysis, well-studied biochemical properties, and their easy detections via secondary antibodies or antigens. Moreover, they can be easily screened in the serum using a noninvasive approach. Consequently, many technical approaches have been developed to study autoantibodies. We used serological proteome analysis (SERPA) for analyzing antibodies in pancreatic cancer patients' sera, and the technique will be discussed in detail. SERPA has several advantages over other approaches currently used such as SEREX (serological analysis of tumor antigens by recombinant cDNA expression cloning) and phage display. SEREX involves the construction of a lambda phage cDNA library from tumor samples to infect bacteria. While library construction is a quite laborious and time-consuming procedure in SEREX, detection of posttranslational modifications that could be fundamental for antibody recognition is a major limitation of both SEREX and phage display techniques. SERPA avoids the time-consuming construction of cDNA libraries. In addition, since it does not rely on bacterial expression of antigens, antigens will have their usual posttranslational modifications preventing false-positive or -negative results in autoantibody profiling.
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Affiliation(s)
- Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies (CeRMS), Turin University Hospital, University of Turin, Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Healthy Sciences, Center for Experimental Research and Medical Studies (CeRMS), Città della Salute e della Scienza di Torino, Turin, Italy
| | - Giorgia Mandili
- Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies (CeRMS), Turin University Hospital, University of Turin, Turin, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies (CeRMS), Turin University Hospital, University of Turin, Turin, Italy.
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26
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Pretta A, Lai E, Persano M, Donisi C, Pinna G, Cimbro E, Parrino A, Spanu D, Mariani S, Liscia N, Dubois M, Migliari M, Impera V, Saba G, Pusceddu V, Puzzoni M, Ziranu P, Scartozzi M. Uncovering key targets of success for immunotherapy in pancreatic cancer. Expert Opin Ther Targets 2021; 25:987-1005. [PMID: 34806517 DOI: 10.1080/14728222.2021.2010044] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. AREAS COVERED In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. EXPERT OPINION The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giovanna Pinna
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Erika Cimbro
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Alissa Parrino
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Rome Italy.,Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
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27
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Lee DH, Choi S, Park Y, Jin HS. Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:ph14101053. [PMID: 34681277 PMCID: PMC8537522 DOI: 10.3390/ph14101053] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 01/18/2023] Open
Abstract
The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.
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Affiliation(s)
- Dong-Hee Lee
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Seunghyun Choi
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;
| | - Yoon Park
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;
- Correspondence: (Y.P.); (H.-s.J.)
| | - Hyung-seung Jin
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: (Y.P.); (H.-s.J.)
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28
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Słotwiński R, Słotwińska SM. Pancreatic cancer and adaptive metabolism in a nutrient-deficient environment. Cent Eur J Immunol 2021; 46:388-394. [PMID: 34764812 PMCID: PMC8574117 DOI: 10.5114/ceji.2021.109693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 05/05/2021] [Indexed: 12/27/2022] Open
Abstract
Despite tremendous progress in the treatment of many cancer types, leading to a significant increase in survival, pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality rates (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the adaptive metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. It was found that blocking selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells, improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation, may inhibit cancer development, increase cancer cell death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention is paid to the adaptive metabolism of pancreatic cancer, including fatty acids, autophagy, macropinocytosis, and deregulated cell-surface glycoproteins, which promotes cancer cell development in an oxygen-deficient and nutrient-poor environment.
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Affiliation(s)
- Robert Słotwiński
- Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Warsaw, Poland
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29
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Wandmacher AM, Letsch A, Sebens S. Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13164235. [PMID: 34439389 PMCID: PMC8391691 DOI: 10.3390/cancers13164235] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Immunotherapeutic agents harness the patient’s immune system to fight cancer cells. Especially immune checkpoint inhibitors, a certain group of immunotherapeutic agents, have recently improved treatment options for many cancer types. Unfortunately, clinical trials testing of these agents in pancreatic cancer patients have not confirmed promising results from laboratory experiments. Several characteristics of pancreatic cancer biology, especially the profound tumour microenvironment that inhibits the successful identification and elimination of tumour cells by immune cells seems to be responsible for the lacking efficacy of immunotherapeutics in pancreatic cancer. We summarise recently published clinical trials investigating immunotherapeutic strategies in pancreatic cancer patients and available data on how these treatments influence pancreatic cancer biology. Moreover, we identify potential strategies to improve experimental and clinical studies in order to generate more conclusive data and improve patient outcomes in the future. Abstract To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC.
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Affiliation(s)
- Anna Maxi Wandmacher
- Department of Internal Medicine II, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (A.M.W.); (A.L.)
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Anne Letsch
- Department of Internal Medicine II, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (A.M.W.); (A.L.)
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Correspondence:
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30
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Abstract
PURPOSE OF REVIEW Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of potential immune interventions for patients with Lynch syndrome polyps and Lynch syndrome-associated carcinomas. RECENT FINDINGS Immunogenic properties of the majority of Lynch syndrome polyps and associated cancers include microsatellite instability leading to a high mutational burden and the development of novel frameshift peptides, i.e., neoantigens. In addition, patients with Lynch syndrome develop T cell responses in the periphery and in the tumor microenvironment (TME) to tumor-associated antigens, and a proinflammatory cytokine TME has also been identified. However, Lynch syndrome lesions also possess immunosuppressive entities such as alterations in MHC class I antigen presentation, TGFβ receptor mutations, regulatory T cells, and upregulation of PD-L1 on tumor-associated lymphocytes. The rich immune microenvironment of Lynch syndrome polyps and associated carcinomas provides an opportunity to employ the spectrum of immune-mediating agents now available to induce and enhance host immune responses and/or to also reduce immunosuppressive entities. These agents can be employed in the so-called prevention trials for the treatment of patients with Lynch syndrome polyps and for trials in patients with Lynch syndrome-associated cancers.
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Affiliation(s)
- Danielle M Pastor
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- NIH Hematology Oncology Fellowship Program, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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31
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Singh K, Yadav D, Jain M, Singh PK, Jin JO. Immunotherapy for the Breast Cancer treatment: Current Evidence and Therapeutic Options. Endocr Metab Immune Disord Drug Targets 2021; 22:212-224. [PMID: 33902424 DOI: 10.2174/1871530321666210426125904] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Breast cancer (BC) stands at the first position among all forms of malignancies found in women globally. The available therapeutic approaches for breast cancer includes chemotherapy, radiation therapy, hormonal therapy and finally surgery. Despite the conventional therapies, in recent years the advance immunology based therapeutics emerge a potential in breast cancer treatment, including immune checkpoint blockades, vaccines and in combination with other treatment strategies. Although, commonly used treatments like trastuzumab/pertuzumab for human epidermal growth factor receptor 2 (Her2) positive and hormone therapy for estrogen receptor (ER) positive and/or progesterone receptor (PR) positive BC are specific but triple negative breast cancer (TNBC) cases remain a great challenge for treatment measures. Immune checkpoint inhibitors (anti-PD-1/ anti-CTLA-4) and anti-cancer vaccines (NeuVax, Muc-1, AVX901, INO-1400 and CEA), either alone or in combination with other therapies have created new paradigm in therapeutic world. In this review, we highlighted the current immunotherapeutic aspects and their ongoing trials towards the better treatment regimen for BC.
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Affiliation(s)
- Kavita Singh
- Centre for Translational Research, School of Studies in Biochemistry, Jiwaji University, Gwalior-474011, Madhya Pradesh, India
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, 712-749, South Korea
| | - Meenu Jain
- ICMR-AMR Diagnostics Taskforce, ECD Division, Indian Council of Medical research, Ansari Nagar, New Delhi-110029, India
| | - Pramod Kumar Singh
- Department of Biosciences, Christian Eminent College, Indore, (MP), India
| | - Jun-O Jin
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai 201508, China
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32
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Koltai T, Reshkin SJ, Carvalho TMA, Cardone RA. Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer. Int J Mol Sci 2021; 22:3953. [PMID: 33921242 PMCID: PMC8069142 DOI: 10.3390/ijms22083953] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell's proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (R.A.C.)
| | - Rosa A. Cardone
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (R.A.C.)
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Abstract
Mucin 1 (MUC1) is a large, transmembrane mucin glycoprotein overexpressed in most adenocarcinomas and plays an important role in tumor progression. Regarding its cellular distribution, biochemical features, and function, tumor-related MUC1 varies from the MUC1 expressed in normal cells. Therefore, targeting MUC1 for cancer immunotherapy and imaging can exploit the difference between cancerous and normal cells. Radiopharmaceuticals have a potential use as carriers for the delivery of radionuclides to tumors for a diagnostic imaging and radiotherapy. Several radiolabeled targeting molecules like peptides, antibodies, and aptamers have been efficiently demonstrated in detecting and treating cancer by targeting MUC1. This review provides a brief overview of the current status of developments and applications of MUC1-targeted radiopharmaceuticals in cancer imaging and therapy.
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Affiliation(s)
- Fariba Maleki
- Research Center of oils and fats, Food and Drug Administration, Kermanshah University of Medical sciences, Kermanshah, Iran
| | - Farzaneh Rezazadeh
- Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Kambiz Varmira
- Research Center of oils and fats, Food and Drug Administration, Kermanshah University of Medical sciences, Kermanshah, Iran
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34
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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35
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Role of targeted immunotherapy for pancreatic ductal adenocarcinoma (PDAC) treatment: An overview. Int Immunopharmacol 2021; 95:107508. [PMID: 33725635 DOI: 10.1016/j.intimp.2021.107508] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/18/2021] [Accepted: 02/12/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors with a high mortality rate and poor survival rate. Depending on the tumor stage, PDAC is either treated by resection surgery, chemotherapies, or radiotherapies. Various chemotherapeutic agents have been used to treat PDAC, alone or in combination. Despite the combinations, chemotherapy exhibits many side-effects leading to an increase in the toxicity profile amongst the PDAC patients. Additionally, these standard chemotherapeutic agents have only a modest impact on patient survival due to their limited efficacy. PDAC was previously considered as an immunologically silent malignancy, but recent findings have demonstrated that effective immune-mediated tumor cell death can be used for its treatment. PDAC is characterized by an immunosuppressive tumor microenvironment accompanied by the major expression of myeloid-derived suppressor cells (MDSC) and M2 tumor-associated macrophages. In contrast, the expression of CD8+ T cells is significantly low. Additionally, infiltration of mast cells in PDAC correlates with the poor prognosis. Immunotherapeutic agents target the immunity mediators and empower them to suppress the tumor and effectively treat PDAC. Different targets are studied and exploited to induce an antitumor immune response in PDAC patients. In recent times, site-specific delivery of immunotherapeutics also gained attention among researchers to effectively treat PDAC. In the present review, existing immunotherapies for PDAC treatment along with their limitations are addressed in detail. The review also includes the pathophysiology, traditional strategies and significance of targeted immunotherapies to combat PDAC effectively. Separately, the identification of ideal targets for the targeted therapy of PDAC is also reviewed exhaustively. Additionally, the review also addresses the applications of targeted immunotherapeutics like checkpoint inhibitors, adoptive T-cell therapy etc.
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Xu Y, Miller CP, Warren EH, Tykodi SS. Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma. Hum Vaccin Immunother 2021; 17:1882-1896. [PMID: 33667140 PMCID: PMC8189101 DOI: 10.1080/21645515.2020.1870846] [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] [Indexed: 12/18/2022] Open
Abstract
In renal-cell carcinoma (RCC), tumor-reactive T-cell responses can occur spontaneously or in response to systemic immunotherapy with cytokines and immune checkpoint inhibitors. Cancer vaccines and engineered T-cell therapies are designed to selectively augment tumor antigen-specific CD8+ T-cell responses with the goal to elicit tumor regression and avoid toxicities associated with nonspecific immunotherapies. In this review, we provide an overview of the central role of T-cell immunity in the treatment of advanced RCC. Clinical outcomes for antigen-targeted vaccines or other T-cell-engaging therapies for RCC are summarized and evaluated, and emerging new strategies to enhance the effectiveness of antigen-specific therapy for RCC are discussed.
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Affiliation(s)
- Yuexin Xu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Chris P Miller
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Edus H Warren
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA
| | - Scott S Tykodi
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA
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37
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O-glycan recognition and function in mice and human cancers. Biochem J 2020; 477:1541-1564. [PMID: 32348475 DOI: 10.1042/bcj20180103] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/01/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023]
Abstract
Protein glycosylation represents a nearly ubiquitous post-translational modification, and altered glycosylation can result in clinically significant pathological consequences. Here we focus on O-glycosylation in tumor cells of mice and humans. O-glycans are those linked to serine and threonine (Ser/Thr) residues via N-acetylgalactosamine (GalNAc), which are oligosaccharides that occur widely in glycoproteins, such as those expressed on the surfaces and in secretions of all cell types. The structure and expression of O-glycans are dependent on the cell type and disease state of the cells. There is a great interest in O-glycosylation of tumor cells, as they typically express many altered types of O-glycans compared with untransformed cells. Such altered expression of glycans, quantitatively and/or qualitatively on different glycoproteins, is used as circulating tumor biomarkers, such as CA19-9 and CA-125. Other tumor-associated carbohydrate antigens (TACAs), such as the Tn antigen and sialyl-Tn antigen (STn), are truncated O-glycans commonly expressed by carcinomas on multiple glycoproteins; they contribute to tumor development and serve as potential biomarkers for tumor presence and stage, both in immunohistochemistry and in serum diagnostics. Here we discuss O-glycosylation in murine and human cells with a focus on colorectal, breast, and pancreatic cancers, centering on the structure, function and recognition of O-glycans. There are enormous opportunities to exploit our knowledge of O-glycosylation in tumor cells to develop new diagnostics and therapeutics.
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38
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Zhang J, Liu D, Saikam V, Gadi MR, Gibbons C, Fu X, Song H, Yu J, Kondengaden SM, Wang PG, Wen L. Machine-Driven Chemoenzymatic Synthesis of Glycopeptide. Angew Chem Int Ed Engl 2020; 59:19825-19829. [PMID: 32677091 PMCID: PMC7733604 DOI: 10.1002/anie.202001124] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/18/2020] [Indexed: 12/28/2022]
Abstract
Historically, researchers have put considerable effort into developing automation systems to prepare natural biopolymers such as peptides and oligonucleotides. The availability of such mature systems has significantly advanced the development of natural science. Over the past twenty years, breakthroughs in automated synthesis of oligosaccharides have also been achieved. A machine-driven platform for glycopeptide synthesis by a reconstructed peptide synthesizer is described. The designed platform is based on the use of an amine-functionalized silica resin to facilitate the chemical synthesis of peptides in organic solvent as well as the enzymatic synthesis of glycan epitopes in the aqueous phase in a single reaction vessel. Both syntheses were performed by a peptide synthesizer in a semiautomated manner.
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Affiliation(s)
- Jiabin Zhang
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Ding Liu
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Varma Saikam
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Madhusudhan R Gadi
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | | | - Xuan Fu
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Heliang Song
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Jin Yu
- Imperial College London, Du Cane Road, London, W12 0NN, UK
| | | | - Peng G Wang
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Liuqing Wen
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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39
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Gao T, Cen Q, Lei H. A review on development of MUC1-based cancer vaccine. Biomed Pharmacother 2020; 132:110888. [PMID: 33113416 DOI: 10.1016/j.biopha.2020.110888] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/05/2020] [Accepted: 10/12/2020] [Indexed: 12/30/2022] Open
Abstract
Mucin 1 (MUC1) is a transmembrane mucin glycoprotein expressed on the surface of almost all epithelial cells. Aberrantly glycosylated MUC1 is associated with cellular transformation from a normal to malignant phenotype in human cancers. Therefore, MUC1 is the major target for the design and development of cancer vaccines. MUC1-based cancer vaccines are a promising strategy for preventing cancer progression and metastasis. This review summarizes the most significant milestones achieved to date in the development of different MUC-1-based vaccine approaches in clinical trials. Further, it provides perspectives for future research that may promote clinical advances in infection-associated cancers.
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Affiliation(s)
- Tong Gao
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
| | - Qianhong Cen
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
| | - Han Lei
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, China.
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40
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Zhang J, Liu D, Saikam V, Gadi MR, Gibbons C, Fu X, Song H, Yu J, Kondengaden SM, Wang PG, Wen L. Machine‐Driven Chemoenzymatic Synthesis of Glycopeptide. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.202001124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Jiabin Zhang
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
| | - Ding Liu
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
| | - Varma Saikam
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
| | | | | | - Xuan Fu
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
| | - Heliang Song
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
| | - Jin Yu
- Imperial College London Du Cane Road London W12 0NN UK
| | | | - Peng G. Wang
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
- School of Medicine Southern University of Science and Technology Shenzhen China
| | - Liuqing Wen
- Department of Chemistry Georgia State University Atlanta GA 30303 USA
- Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
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41
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Wang S, You L, Dai M, Zhao Y. Mucins in pancreatic cancer: A well-established but promising family for diagnosis, prognosis and therapy. J Cell Mol Med 2020; 24:10279-10289. [PMID: 32745356 PMCID: PMC7521221 DOI: 10.1111/jcmm.15684] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/12/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Mucins are a family of multifunctional glycoproteins that mostly line the surface of epithelial cells in the gastrointestinal tract and exert pivotal roles in gut lubrication and protection. Pancreatic cancer is a lethal disease with poor early diagnosis, limited therapeutic effects, and high numbers of cancer‐related deaths. In this review, we introduce the expression profiles of mucins in the normal pancreas, pancreatic precursor neoplasia and pancreatic cancer. Mucins in the pancreas contribute to biological processes such as the protection, lubrication and moisturization of epithelial tissues. They also participate in the carcinogenesis of pancreatic cancer and are used as diagnostic biomarkers and therapeutic targets. Herein, we discuss the important roles of mucins that lead to the lethality of pancreatic adenocarcinoma, particularly MUC1, MUC4, MUC5AC and MUC16 in disease progression, and present a comprehensive analysis of the clinical application of mucins and their promising roles in cancer treatment to gain a better understanding of the role of mucins in pancreatic cancer.
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Affiliation(s)
- Shunda Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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42
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Schizas D, Charalampakis N, Kole C, Economopoulou P, Koustas E, Gkotsis E, Ziogas D, Psyrri A, Karamouzis MV. Immunotherapy for pancreatic cancer: A 2020 update. Cancer Treat Rev 2020; 86:102016. [PMID: 32247999 DOI: 10.1016/j.ctrv.2020.102016] [Citation(s) in RCA: 283] [Impact Index Per Article: 56.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic adenocarcinoma (PAC) is associated with extremely poor prognosis and remains a lethal malignancy. The main cure for PAC is surgical resection. Further treatment modalities, such as surgery, chemotherapy, radiotherapy and other locoregional therapies provide low survival rates. Currently, many clinical trials seek to assess the efficacy of immunotherapeutic strategies in PAC, including immune checkpoint inhibitors, cancer vaccines, adoptive cell transfer, combinations with other immunotherapeutic agents, chemoradiotherapy or other molecularly targeted agents; however, none of these studies have shown practice changing results. There seems to be a synergistic effect with increased response rates when a combinatorial approach of immunotherapy in conjunction with other modalities is being exploited. In this review, we illustrate the current role of immunotherapy in PAC.
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Affiliation(s)
- Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | | | - Christo Kole
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Panagiota Economopoulou
- Department of Internal Medicine, Section of Medical Oncology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthymios Gkotsis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Dimitrios Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Amanda Psyrri
- Department of Internal Medicine, Section of Medical Oncology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, National and Kapodistrian University of Athens, Athens, Greece
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43
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Yu H, Ye C, Li J, Pan C, Lin W, Chen H, Zhou Z, Ye Y. An altered HLA-A0201-restricted MUC1 epitope that could induce more efficient anti-tumor effects against gastric cancer. Exp Cell Res 2020; 390:111953. [PMID: 32156601 DOI: 10.1016/j.yexcr.2020.111953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 12/30/2022]
Abstract
MUC1 is a tumor-associated antigen (TAA) overexpressed in many tumor types, which makes it an attractive target for cancer immunotherapy. However, this marker is a non-mutated antigen without high immunogenicity. In this study, we designed several new altered peptides by replacing amino acids in their sequences, which were derived from a low-affinity MUC1 peptide, thus bypassing immune tolerance. Compared to the wild-type (WT) peptide, the altered MUC1 peptides (MUC11081-1089L2, MUC11156-1164L2, MUC11068-1076Y1) showed higher affinity to the HLA-A0201 molecule and stronger immunogenicity. Furthermore, these altered peptides resulted in the generation of more cytotoxic T lymphocytes (CTLs) that could cross-recognize gastric cancer cells expressing WT MUC1 peptides, in an HLA-A0201-restricted manner. In addition, M1.1 (MUC1950-958), a promising antitumor peptide that has been tested in multiple tumors, was not able to induce stronger antitumor responses. Collectively, our results demonstrated that altered peptides from MUC1, as potential HLA-A0201-restricted CTL epitopes, could serve as peptide vaccines or constitute components of peptide-loaded dendritic cell vaccines for gastric cancer treatment.
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Affiliation(s)
- Huahui Yu
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Chunmei Ye
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Jieyu Li
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Chunli Pan
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China
| | - Wansong Lin
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Huijing Chen
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Zhifeng Zhou
- Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China
| | - Yunbin Ye
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China; Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, Fujian Province, China.
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44
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Syrkina MS, Vassetzky YS, Rubtsov MA. MUC1 Story: Great Expectations, Disappointments and the Renaissance. Curr Med Chem 2019; 26:554-563. [PMID: 28820070 DOI: 10.2174/0929867324666170817151954] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 07/03/2017] [Accepted: 07/03/2017] [Indexed: 11/22/2022]
Abstract
In the course of studying human mucin MUC1, the attitude towards this molecule has been changing time and again. Initially, the list of presumable functions of MUC1 was restricted to protecting and lubricating epithelium. To date, it is assumed to play an important role in cell signaling as well as in all stages of oncogenesis, from malignant cell transformation to tumor dissemination. The story of MUC1 is full of hopes and disappointments. However, the scientific interest to MUC1 has never waned, and the more profoundly it has been investigated, the clearer its hidden potential turned to be disclosed. The therapeutic potential of mucin MUC1 has already been noted by various scientific groups at the early stages of research. Over forty years ago, the first insights into MUC1 functions became a strong ground for considering this molecule as potential target for anticancer therapy. Therefore, this direction of research has always been of particular interest and practical importance. More than 200 papers on MUC1 were published in 2016; the majority of them are dedicated to MUC1-related anticancer diagnostics and therapeutics. Here we review the history of MUC1 studies from the very first attempts to reveal its functions to the ongoing renaissance.
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Affiliation(s)
- Marina S Syrkina
- Department of Molecular Biology, Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.,LIA LFR2O (LIA French-Russian Cancer Research laboratory) Villejuif, France - Moscow, Russian Federation.,Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Yegor S Vassetzky
- LIA LFR2O (LIA French-Russian Cancer Research laboratory) Villejuif, France - Moscow, Russian Federation.,UMR8126, Université Paris Sud - Paris Saclay, CNRS, Institut Gustave Roussy, 94805 Villejuif, France.,A.N. Belozersky Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.,Koltzov Institute of Developmental Biology, Moscow, Russian Federation
| | - Mikhail A Rubtsov
- Department of Molecular Biology, Faculty of Biology, M.V. Lomonosov Moscow State University, Moscow, Russian Federation.,LIA LFR2O (LIA French-Russian Cancer Research laboratory) Villejuif, France - Moscow, Russian Federation.,Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation.,Department of Biochemistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
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Abstract
PURPOSE OF REVIEW Despite all efforts, pancreatic ductal adenocarcinoma (PDAC) remains a disease that causes substantial morbidity and mortality, with a 5-year survival rate of 7%. Innovative paradigms for treating PDAC are urgently needed. RECENT FINDINGS We discuss the advances and difficulties in using immunotherapy and developing immunotherapeutic vaccines for PDAC. Current excitement about antigen-specific immunotherapy has been propelled by advances in multiple areas, such as next-generation sequencing to identify neoantigens and manufacturing to produce immunotherapeutic vaccines. Antigen-specific immunotherapy is being actively explored in clinical trials. As the field of immunotherapy matures and as our understanding of the complex interactions between tumor and host develops, we hope to identify new methods for treating and managing PDAC.
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Affiliation(s)
- Annie A Wu
- Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA
| | - Elizabeth Jaffee
- Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA
| | - Valerie Lee
- Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA.
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46
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Banerjee K, Gautam SK, Kshirsagar P, Ross KA, Spagnol G, Sorgen P, Wannemuehler MJ, Narasimhan B, Solheim JC, Kumar S, Batra SK, Jain M. Amphiphilic polyanhydride-based recombinant MUC4β-nanovaccine activates dendritic cells. Genes Cancer 2019; 10:52-62. [PMID: 31258832 PMCID: PMC6584211 DOI: 10.18632/genesandcancer.189] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Mucin 4 (MUC4) is a high molecular weight glycoprotein that is differentially overexpressed in pancreatic cancer (PC), functionally contributes to disease progression, and correlates with poor survival. Further, due to its aberrant glycosylation and extensive splicing, MUC4 is a potential target for cancer immunotherapy. Our previous studies have demonstrated the utility of amphiphilic polyanhydride nanoparticles as a useful platform for the development of protein-based prophylactic and therapeutic vaccines. In the present study, we encapsulated purified recombinant human MUC4-beta (MUC4β) protein in polyanhydride (20:80 CPTEG:CPH) nanoparticles (MUC4β-nanovaccine) and evaluated its ability to activate dendritic cells and induce adaptive immunity. Immature dendritic cells when pulsed with MUC4β-nanovaccine exhibited significant increase in the surface expressions of MHC I and MHC II and costimulatory molecules (CD80 and CD86), as well as, secretion of pro-inflammatory cytokines (IFN-γ, IL-6, and IL-12) as compared to cells exposed to MUC4β alone or MUC4β mixed with blank nanoparticles (MUC4β+NP). Following immunization, as compared to the other formulations, MUC4β-nanovaccine elicited higher IgG2b to IgG1 ratio of anti-MUC4β-antibodies suggesting a predominantly Th1-like class switching. Thus, our findings demonstrate MUC4β-nanovaccine as a novel platform for PC immunotherapy.
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Affiliation(s)
- Kasturi Banerjee
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Prakash Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kathleen A Ross
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA
| | - Gaelle Spagnol
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paul Sorgen
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael J Wannemuehler
- Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, USA.,Nanovaccine Institute, Ames, IA and Omaha, NE, USA
| | - Balaji Narasimhan
- Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, USA.,Nanovaccine Institute, Ames, IA and Omaha, NE, USA
| | - Joyce C Solheim
- The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Nanovaccine Institute, Ames, IA and Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Nanovaccine Institute, Ames, IA and Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Nanovaccine Institute, Ames, IA and Omaha, NE, USA
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47
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Perkhofer L, Beutel AK, Ettrich TJ. Immunotherapy: Pancreatic Cancer and Extrahepatic Biliary Tract Cancer. Visc Med 2019; 35:28-37. [PMID: 31312647 DOI: 10.1159/000497291] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 01/28/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic biliary tract cancer (BTC) are among the malignancies with the highest morbidity and mortality. Despite increasing knowledge on biology and novel therapies, outcome remains poor in these patients. Recent progress in immunotherapies created new hopes in the treatment of PDAC and extrahepatic BTC. Several trials tested immunotherapies in various therapeutic situations as monotherapies or in combinations. Although responses were seen in some of the trials, the value of immunotherapy in PDAC and extrahepatic BTC remains unclear in the current situation, especially regarding the complex biological characteristics with a high stroma component, intrinsic resistance mechanisms and an immunosuppressive, hypoxic microenvironment. These major hurdles have to be taken into account and overcome if immunotherapies should be successful in these tumor entities. Thereby, combinational approaches that allow on the one hand targeted therapy and on the other restore or boost the function of immune cells are promising.
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Affiliation(s)
- Lukas Perkhofer
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany
| | - Alica K Beutel
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany
| | - Thomas J Ettrich
- Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany
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48
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Chen ST, Kuo TC, Liao YY, Lin MC, Tien YW, Huang MC. Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. Oncogene 2018; 37:6041-6053. [PMID: 29993037 PMCID: PMC6237765 DOI: 10.1038/s41388-018-0403-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/28/2018] [Accepted: 06/14/2018] [Indexed: 12/18/2022]
Abstract
Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.
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Affiliation(s)
- Syue-Ting Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Yu Liao
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Chun Lin
- Department of Otolaryngology, National Taiwan University Hospital, Hsinchu, Hsinchu, Taiwan
- National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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49
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Matsui H, Hazama S, Shindo Y, Nagano H. Combination treatment of advanced pancreatic cancer using novel vaccine and traditional therapies. Expert Rev Anticancer Ther 2018; 18:1205-1217. [DOI: 10.1080/14737140.2018.1531707] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Hiroto Matsui
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
- Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Yamaguchi, Japan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
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50
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Abstract
The question of whether human tumors express antigens that can be recognized by the immune system has been answered with a resounding YES. Most were identified through spontaneous antitumor humoral and cellular immune responses found in cancer patients and include peptides, glycopeptides, phosphopeptides, viral peptides, and peptides resulting from common mutations in oncogenes and tumor-suppressor genes, or common gene fusion events. Many have been extensively tested as candidates for anticancer vaccines. More recently, attention has been focused on the potentially large number of unique tumor antigens, mutated neoantigens, that are the predicted products of the numerous mutations revealed by exome sequencing of primary tumors. Only a few have been confirmed as targets of spontaneous immunity and immunosurveillance, and even fewer have been tested in preclinical and clinical settings. The field has been divided for a long time on the relative importance of shared versus mutated antigens in tumor surveillance and as candidates for vaccines. This question will eventually need to be answered in a head to head comparison in well-designed clinical trials. One advantage that shared antigens have over mutated antigens is their potential to be used in vaccines for primary cancer prevention. Cancer Immunol Res; 5(5); 347-54. ©2017 AACR.
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Affiliation(s)
- Olivera J Finn
- Department of Immunology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
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