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1
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Liu N, Wang X, Wang Z, Kan Y, Fang Y, Gao J, Kong X, Wang J. Nanomaterials-driven in situ vaccination: a novel frontier in tumor immunotherapy. J Hematol Oncol 2025; 18:45. [PMID: 40247328 PMCID: PMC12007348 DOI: 10.1186/s13045-025-01692-4] [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: 10/09/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.
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Affiliation(s)
- Naimeng Liu
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiangyu Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yonemori Kan
- Department of Medical Oncology, National Cancer Center Hospital (NCCH), 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jidong Gao
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518127, China.
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Sanati M, Figueroa-Espada CG, Han EL, Mitchell MJ, Yavari SA. Bioengineered Nanomaterials for siRNA Therapy of Chemoresistant Cancers. ACS NANO 2024; 18:34425-34463. [PMID: 39666006 DOI: 10.1021/acsnano.4c11259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Chemoresistance remains a long-standing challenge after cancer treatment. Over the last two decades, RNA interference (RNAi) has emerged as a gene therapy modality to sensitize cancer cells to chemotherapy. However, the use of RNAi, specifically small-interfering RNA (siRNA), is hindered by biological barriers that limit its intracellular delivery. Nanoparticles can overcome these barriers by protecting siRNA in physiological environments and facilitating its delivery to cancer cells. In this review, we discuss the development of nanomaterials for siRNA delivery in cancer therapy, current challenges, and future perspectives for their implementation to overcome cancer chemoresistance.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand 97178, Iran
| | - Christian G Figueroa-Espada
- Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, Pennsylvania 19104, United States
| | - Emily L Han
- Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, Pennsylvania 19104, United States
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, Pennsylvania 19104, United States
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Saber Amin Yavari
- Department of Orthopedics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 Utrecht, The Netherlands
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3
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Hwang SM, Awasthi D, Jeong J, Sandoval TA, Chae CS, Ramos Y, Tan C, Marin Falco M, Salvagno C, Emmanuelli A, McBain IT, Mishra B, Ivashkiv LB, Zamarin D, Cantillo E, Chapman-Davis E, Holcomb K, Morales DK, Yu X, Rodriguez PC, Conejo-Garcia JR, Kaczocha M, Vähärautio A, Song M, Cubillos-Ruiz JR. Transgelin 2 guards T cell lipid metabolism and antitumour function. Nature 2024; 635:1010-1018. [PMID: 39443795 PMCID: PMC11949091 DOI: 10.1038/s41586-024-08071-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 09/18/2024] [Indexed: 10/25/2024]
Abstract
Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
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Affiliation(s)
- Sung-Min Hwang
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Deepika Awasthi
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Jieun Jeong
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tito A Sandoval
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Chang-Suk Chae
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Research Institute, National Cancer Center, Goyang, Republic of Korea
| | - Yusibeska Ramos
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Chen Tan
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Matías Marin Falco
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Camilla Salvagno
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Alexander Emmanuelli
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Ian T McBain
- Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Bikash Mishra
- Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
| | - Lionel B Ivashkiv
- Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
| | - Dmitriy Zamarin
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Evelyn Cantillo
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Eloise Chapman-Davis
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Kevin Holcomb
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Diana K Morales
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Xiaoqing Yu
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Paulo C Rodriguez
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jose R Conejo-Garcia
- Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke School of Medicine, Durham, NC, USA
| | - Martin Kaczocha
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
- Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA
- Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Anna Vähärautio
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Foundation for the Finnish Cancer Institute, Helsinki, Finland
| | - Minkyung Song
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Departments of Integrative Biotechnology and of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
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4
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Kaur P, Singh SK, Mishra MK, Singh S, Singh R. Nanotechnology for boosting ovarian cancer immunotherapy. J Ovarian Res 2024; 17:202. [PMID: 39402681 PMCID: PMC11475952 DOI: 10.1186/s13048-024-01507-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 08/28/2024] [Indexed: 10/19/2024] Open
Abstract
Ovarian cancer, often referred to as the "silent killer," is notoriously difficult to detect in its early stages, leading to a poor prognosis for many patients. Diagnosis is often delayed until the cancer has advanced, primarily due to its ambiguous and frequently occurring clinical symptoms. Ovarian cancer leads to more deaths than any other cancer of the female reproductive system. The main reasons for the high mortality rates include delayed diagnosis and resistance to treatment. As a result, there is an urgent need for improved diagnostic and treatment options for ovarian cancer. The standard treatments typically involve debulking surgery along with platinum-based chemotherapies. Among patients with advanced-stage cancer who initially respond to current therapies, 50-75% experience a recurrence. Recently, immunotherapy-based approaches to enhance the body's immune response to combat tumor growth have shown promise. Immune checkpoint inhibitors have shown promising results in treating other types of tumors. However, in ovarian cancer, only a few of these inhibitors have been effective because the tumor's environment suppresses the immune system and creates barriers for treatment. This hampers the effectiveness of existing immunotherapies. Nonetheless, advanced immunotherapy techniques and delivery systems based on nanotechnology hold promise for overcoming these challenges.
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Affiliation(s)
- Prabhjot Kaur
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
| | - Santosh Kumar Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
| | - Manoj K Mishra
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36014, USA
| | - Shailesh Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, 30310, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA.
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
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5
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Wang Y, Zhang W, Li T, Liu M, Gao M, Li X, Chen Y, Song Y, Li W, Du C, Wang F, Liu L. Identification of potential immune-related mechanisms related to the development of multiple myeloma. Chin Med J (Engl) 2024; 137:1603-1613. [PMID: 38844445 PMCID: PMC11230759 DOI: 10.1097/cm9.0000000000003116] [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: 07/11/2023] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND Although significant advances have been made in the treatment of multiple myeloma (MM), leading to unprecedented response and survival rates among patients, the majority eventually relapse, and a cure remains elusive. This situation is closely related to an incomplete understanding of the immune microenvironment, especially monocytes/macrophages in patients with treatment-naïve MM. The aim of this study was to provide insight into the immune microenvironment, especially monocytes/macrophages, in patients with treatment-naïve MM. METHODS This study used the single-cell RNA sequencing (scRNA-seq) data of both patients with MM and heathy donors to identify immune cells, including natural killer (NK) cells, T cells, dendritic cells (DCs), and monocytes/macrophages. Transcriptomic data and flow cytometry analysis of monocytes/macrophages were used to further examine the effect of monocytes/macrophages in treatment-naïve MM patients. RESULTS A significant difference was observed between the bone marrow (BM) immune cells of the healthy controls and treatment-naïve MM patients through scRNA-seq. It is noteworthy that, through an scRNA-seq data analysis, this study found that interferon (IFN)-induced NK/T cells, terminally differentiated effector memory (TEMRA) cells, T-helper cells characterized by expression of IFN-stimulated genes (ISG + Th cells), IFN-responding exhausted T cells, mannose receptor C-type 1 (MRC1) + DCs, IFN-responding DCs, MHCII + DCs, and immunosuppressive monocytes/macrophages were enriched in patients with treatment-naïve MM. Significantly, transcriptomic data of monocytes/macrophages demonstrated that "don't eat me"-related genes and IFN-induced genes increase in treatment-naïve MM patients. Furthermore, scRNA-seq, transcriptomic data, and flow cytometry also showed an increased proportion of CD16 + monocytes/macrophages and expression level of CD16. Cell-cell communication analysis indicated that monocytes/macrophages, whose related important signaling pathways include migration inhibitory factor (MIF) and interleukin 16 (IL-16) signaling pathway, are key players in treatment-naïve MM patients. CONCLUSIONS Our findings provide a comprehensive and in-depth molecular characterization of BM immune cell census in MM patients, especially for monocytes/macrophages. Targeting macrophages may be a novel treatment strategy for patients with MM.
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Affiliation(s)
- Yaomei Wang
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Wenli Zhang
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Tiandong Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Mengmeng Liu
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Mengya Gao
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Xinqing Li
- Department of Clinical Medicine, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yufei Chen
- The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yongping Song
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chunyan Du
- Laboratory Animal Center, School of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Fang Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Lina Liu
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
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Binder AK, Bremm F, Dörrie J, Schaft N. Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential. Int J Mol Sci 2024; 25:7275. [PMID: 39000381 PMCID: PMC11242727 DOI: 10.3390/ijms25137275] [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: 05/06/2024] [Revised: 06/19/2024] [Accepted: 06/29/2024] [Indexed: 07/16/2024] Open
Abstract
The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.
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Affiliation(s)
- Amanda Katharina Binder
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Franziska Bremm
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
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Lotfalizadeh N, Sadr S, Morovati S, Lotfalizadeh M, Hajjafari A, Borji H. A potential cure for tumor-associated immunosuppression by Toxoplasma gondii. Cancer Rep (Hoboken) 2024; 7:e1963. [PMID: 38109851 PMCID: PMC10850000 DOI: 10.1002/cnr2.1963] [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: 07/24/2023] [Revised: 11/06/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Recently, immunotherapy has become very hopeful for cancer therapy. Cancer treatment through immunotherapy has excellent specificity and less toxicity than conventional chemoradiotherapy. Pathogens have been used in cancer immunotherapy for a long time. The current study aims to evaluate the possibility of Toxoplasma gondii (T. gondii) as a probable treatment for cancers such as melanoma, breast, ovarian, lung, and pancreatic cancer. RECENT FINDINGS Nonreplicating type I uracil auxotrophic mutants of T. gondii can stimulate immune responses against tumors by reverse immunosuppression at the cellular level. T. gondii can be utilized to research T helper 1 (Th1) cell immunity in intracellular infections. Avirulent T. gondii uracil auxotroph vaccine can change the tumor's immunosuppression and improve the production of type 1 helper cell cytokines, i.e., Interferon-gamma (IFN-γ) and Interleukin-12 (IL-12) and activate tumor-related Cluster of Differentiation 8 (CD8+) T cells to identify and destroy cancer cells. The T. gondii profilin protein, along with T. gondii secreted proteins, have been found to exhibit promising properties in the treatment of various cancers. These proteins are being studied for their potential to inhibit tumor growth and enhance the effectiveness of cancer therapies. Their unique mechanisms of action make them valuable candidates for targeted interventions in ovarian cancer, breast cancer, pancreatic cancer, melanoma, and lung cancer treatments. CONCLUSION In summary, the study underscores the significant potential of harnessing T. gondii, including its diverse array of proteins and antigens, particularly in its avirulent form, as a groundbreaking approach in cancer immunotherapy.
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Affiliation(s)
- Narges Lotfalizadeh
- Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
| | - Soheil Sadr
- Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
| | - Solmaz Morovati
- Division of Biotechnology, Department of Pathobiology, School of Veterinary MedicineShiraz UniversityShirazIran
| | - Mohammadhassan Lotfalizadeh
- Board Certificate Oral and Maxillofacial RadiologistNorth Khorasan University of Medical Sciences (NKUMS)BojnurdIran
| | - Ashkan Hajjafari
- Department of Pathobiology, Faculty of Veterinary MedicineIslamic Azad University, Science and Research BranchTehranIran
| | - Hassan Borji
- Department of Pathobiology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
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8
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Hwang SM, Awasthi D, Jeong J, Sandoval TA, Chae CS, Ramos Y, Tan C, Falco MM, McBain IT, Mishra B, Ivashkiv LB, Zamarin D, Cantillo E, Chapman-Davis E, Holcomb K, Morales DK, Rodriguez PC, Conejo-Garcia JR, Kaczocha M, Vähärautio A, Song M, Cubillos-Ruiz JR. Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function. RESEARCH SQUARE 2023:rs.3.rs-3683989. [PMID: 38168227 PMCID: PMC10760247 DOI: 10.21203/rs.3.rs-3683989/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells4,5. Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8+ T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8+ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8+ T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
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Affiliation(s)
- Sung-Min Hwang
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Deepika Awasthi
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Jieun Jeong
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Tito A. Sandoval
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Chang-Suk Chae
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Yusibeska Ramos
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
| | - Chen Tan
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Matías Marin Falco
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Ian T. McBain
- Weill Cornell Graduate School of Medical Sciences. New York, NY 10065. USA
| | - Bikash Mishra
- Weill Cornell Graduate School of Medical Sciences. New York, NY 10065. USA
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
| | - Lionel B. Ivashkiv
- Weill Cornell Graduate School of Medical Sciences. New York, NY 10065. USA
- HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
| | - Dmitriy Zamarin
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Evelyn Cantillo
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Eloise Chapman-Davis
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Kevin Holcomb
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Diana K. Morales
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
| | - Paulo C. Rodriguez
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute. Tampa, FL, USA
| | - Jose R. Conejo-Garcia
- Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC 27710, USA
- Duke Cancer Institute, Duke School of Medicine, Durham, NC 27710, USA
| | - Martin Kaczocha
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
- Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA
- Stony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Anna Vähärautio
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Foundation for the Finnish Cancer Institute, Helsinki, Finland
| | - Minkyung Song
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
| | - Juan R. Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medicine. New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine. New York, NY 10065, USA
- Weill Cornell Graduate School of Medical Sciences. New York, NY 10065. USA
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9
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Zeyn Y, Hobernik D, Wilk U, Pöhmerer J, Hieber C, Medina-Montano C, Röhrig N, Strähle CF, Thoma-Kress AK, Wagner E, Bros M, Berger S. Transcriptional Targeting of Dendritic Cells Using an Optimized Human Fascin1 Gene Promoter. Int J Mol Sci 2023; 24:16938. [PMID: 38069260 PMCID: PMC10706967 DOI: 10.3390/ijms242316938] [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: 10/27/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Deeper knowledge about the role of the tumor microenvironment (TME) in cancer development and progression has resulted in new strategies such as gene-based cancer immunotherapy. Whereas some approaches focus on the expression of tumoricidal genes within the TME, DNA-based vaccines are intended to be expressed in antigen-presenting cells (e.g., dendritic cells, DCs) in secondary lymphoid organs, which in turn induce anti-tumor T cell responses. Besides effective delivery systems and the requirement of appropriate adjuvants, DNA vaccines themselves need to be optimized regarding efficacy and selectivity. In this work, the concept of DC-focused transcriptional targeting was tested by applying a plasmid encoding for the luciferase reporter gene under the control of a derivative of the human fascin1 gene promoter (pFscnLuc), comprising the proximal core promoter fused to the normally more distantly located DC enhancer region. DC-focused activity of this reporter construct was confirmed in cell culture in comparison to a standard reporter vector encoding for luciferase under the control of the strong ubiquitously active cytomegalovirus promoter and enhancer (pCMVLuc). Both plasmids were also compared upon intravenous administration in mice. The organ- and cell type-specific expression profile of pFscnLuc versus pCMVLuc demonstrated favorable activity especially in the spleen as a central immune organ and within the spleen in DCs.
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Affiliation(s)
- Yanira Zeyn
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, 55131 Mainz, Germany; (Y.Z.); (D.H.); (C.H.); (C.M.-M.); (N.R.)
| | - Dominika Hobernik
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, 55131 Mainz, Germany; (Y.Z.); (D.H.); (C.H.); (C.M.-M.); (N.R.)
| | - Ulrich Wilk
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScience, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; (U.W.); (J.P.); (E.W.)
| | - Jana Pöhmerer
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScience, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; (U.W.); (J.P.); (E.W.)
| | - Christoph Hieber
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, 55131 Mainz, Germany; (Y.Z.); (D.H.); (C.H.); (C.M.-M.); (N.R.)
| | - Carolina Medina-Montano
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, 55131 Mainz, Germany; (Y.Z.); (D.H.); (C.H.); (C.M.-M.); (N.R.)
| | - Nadine Röhrig
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, 55131 Mainz, Germany; (Y.Z.); (D.H.); (C.H.); (C.M.-M.); (N.R.)
| | - Caroline F. Strähle
- Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; (C.F.S.); (A.K.T.-K.)
| | - Andrea K. Thoma-Kress
- Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; (C.F.S.); (A.K.T.-K.)
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScience, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; (U.W.); (J.P.); (E.W.)
| | - Matthias Bros
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, 55131 Mainz, Germany; (Y.Z.); (D.H.); (C.H.); (C.M.-M.); (N.R.)
| | - Simone Berger
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScience, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; (U.W.); (J.P.); (E.W.)
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10
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Zhang Z, Yao S, Hu Y, Zhao X, Lee RJ. Application of lipid-based nanoparticles in cancer immunotherapy. Front Immunol 2022; 13:967505. [PMID: 36003395 PMCID: PMC9393708 DOI: 10.3389/fimmu.2022.967505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy is revolutionizing the clinical management of patients with different cancer types by sensitizing autologous or allogenic immune cells to the tumor microenvironment which eventually leads to tumor cell lysis without rapidly killing normal cells. Although immunotherapy has been widely demonstrated to be superior to chemotherapies, only a few populations of patients with specific cancer types respond to such treatment due to the failure of systemic immune activation. In addition, severe immune-related adverse events are rapidly observed when patients with very few responses are given higher doses of such therapies. Recent advances of lipid-based nanoparticles (NPs) development have made it possible to deliver not only small molecules but also mRNAs to achieve systemic anticancer immunity through cytotoxic immune cell activation, checkpoint blockade, and chimeric antigen receptor cell therapies, etc. This review summarized recent development and applications of LNPs in anticancer immunotherapy. The diversity of lipid-based NPs would encapsulate payloads with different structures and molecular weights to achieve optimal antitumor immunity through multiple mechanisms of action. The discussion about the components of lipid-based NPs and their immunologic payloads in this review hopefully shed more light on the future direction of anticancer immunotherapy.
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Affiliation(s)
- Zhongkun Zhang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States
| | - Siyu Yao
- Department of Food Science and Technology, The Ohio State University, Columbus, OH, United States
| | - Yingwen Hu
- The Whiteoak Group, Inc., Rockville, MD, United States
| | - Xiaobin Zhao
- The Whiteoak Group, Inc., Rockville, MD, United States
| | - Robert J. Lee
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States
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11
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Shahgordi S, Oroojalian F, Hashemi E, Hashemi M. Recent advances in development of nano-carriers for immunogene therapy in various complex disorders. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:134-147. [PMID: 35655600 PMCID: PMC9124536 DOI: 10.22038/ijbms.2022.59718.13245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 01/01/2022] [Indexed: 01/25/2023]
Abstract
Immunotherapy is a novel preference for the treatment of various complex diseases. Considering the application of varying agents for suppression or activation of the immune system, immunogene therapy was confirmed to stand as a proper alternative for other immunotherapeutic strategies due to its capability in targeting cells with more specificity that leads to controlling the expression of therapeutic genes. This method facilitates the local and single-dose application of most gene therapies that result in the usage of high therapeutic doses with a low risk of systemic side effects while being cost-efficient in long-term administrations. However, the existing barriers between the administration site and cell nucleus limited the clinical uses of genetic materials. These challenges can be overcome through the promising method of exerting non-carriers with high stability, low toxicity/immunogenicity, and simple modifications. In this study, we attempted to review the potential of nanoparticle application throughout the immunogene therapy of different diseases including cancer, microbial diseases, allergies, inflammatory bowel disease, rheumatoid arthritis, and respiratory infections. We included the outline of some challenges and opportunities in regards to the delivery of genetic materials that are based on nano-systems through immunotherapy of these disorders. Next to the promising future of these vectors, more detailed analyses are required to overcome the current limitations in clinical approaches.
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Affiliation(s)
- Sanaz Shahgordi
- Immunology Department, Faculty of Medicine, Golestan University of Medical Science, Gorgan, Iran, Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ezzat Hashemi
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Maryam Hashemi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran, Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad, University of Medical Sciences, Mashhad, Iran,Corresponding author: Maryam Hashemi. Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Tel: +98-51-31801219;
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12
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Gorbet MJ, Singh A, Mao C, Fiering S, Ranjan A. Using nanoparticles for in situ vaccination against cancer: mechanisms and immunotherapy benefits. Int J Hyperthermia 2021; 37:18-33. [PMID: 33426995 DOI: 10.1080/02656736.2020.1802519] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy to treat cancer is now an established clinical approach. Immunotherapy can be applied systemically, as done with checkpoint blockade antibodies, but it can also be injected directly into identified tumors, in a strategy of in situ vaccination (ISV). ISV is designed to stimulate a strong local antitumor immune response involving both innate and adaptive immune cells, and through this generate a systemic antitumor immune response against metastatic tumors. A variety of ISVs have been utilized to generate an immunostimulatory tumor microenvironment (TME). These include attenuated microorganisms, recombinant proteins, small molecules, physical disruptors of TME (alternating magnetic and focused ultrasound heating, photothermal therapy, and radiotherapy), and more recently nanoparticles (NPs). NPs are attractive and unique since they can load multiple drugs or other reagents to influence immune and cancer cell functions in the TME, affording a unique opportunity to stimulate antitumor immunity. Here, we describe the NP-ISV therapeutic mechanisms, review chemically synthesized NPs (i.e., liposomes, polymeric, chitosan-based, inorganic NPs, etc.), biologically derived NPs (virus and bacteria-based NPs), and energy-activated NP-ISVs in the context of their use as local ISV. Data suggests that NP-ISVs can enhance outcomes of immunotherapeutic regimens including those utilizing tumor hyperthermia and checkpoint blockade therapies.
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Affiliation(s)
| | - Akansha Singh
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Chenkai Mao
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Steven Fiering
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center at Dartmouth and Dartmouth Hitchcock, Lebanon, NH, USA
| | - Ashish Ranjan
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
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13
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Chauhan DS, Dhasmana A, Laskar P, Prasad R, Jain NK, Srivastava R, Jaggi M, Chauhan SC, Yallapu MM. Nanotechnology synergized immunoengineering for cancer. Eur J Pharm Biopharm 2021; 163:72-101. [PMID: 33774162 PMCID: PMC8170847 DOI: 10.1016/j.ejpb.2021.03.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/06/2021] [Accepted: 03/15/2021] [Indexed: 12/26/2022]
Abstract
Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic(s). As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, and delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies availed in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment.
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Affiliation(s)
- Deepak S Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Partha Laskar
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Rajendra Prasad
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Nishant K Jain
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA.
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14
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Kumar R, Santa Chalarca CF, Bockman MR, Bruggen CV, Grimme CJ, Dalal RJ, Hanson MG, Hexum JK, Reineke TM. Polymeric Delivery of Therapeutic Nucleic Acids. Chem Rev 2021; 121:11527-11652. [PMID: 33939409 DOI: 10.1021/acs.chemrev.0c00997] [Citation(s) in RCA: 196] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The advent of genome editing has transformed the therapeutic landscape for several debilitating diseases, and the clinical outlook for gene therapeutics has never been more promising. The therapeutic potential of nucleic acids has been limited by a reliance on engineered viral vectors for delivery. Chemically defined polymers can remediate technological, regulatory, and clinical challenges associated with viral modes of gene delivery. Because of their scalability, versatility, and exquisite tunability, polymers are ideal biomaterial platforms for delivering nucleic acid payloads efficiently while minimizing immune response and cellular toxicity. While polymeric gene delivery has progressed significantly in the past four decades, clinical translation of polymeric vehicles faces several formidable challenges. The aim of our Account is to illustrate diverse concepts in designing polymeric vectors towards meeting therapeutic goals of in vivo and ex vivo gene therapy. Here, we highlight several classes of polymers employed in gene delivery and summarize the recent work on understanding the contributions of chemical and architectural design parameters. We touch upon characterization methods used to visualize and understand events transpiring at the interfaces between polymer, nucleic acids, and the physiological environment. We conclude that interdisciplinary approaches and methodologies motivated by fundamental questions are key to designing high-performing polymeric vehicles for gene therapy.
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Affiliation(s)
- Ramya Kumar
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | | | - Matthew R Bockman
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Craig Van Bruggen
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Christian J Grimme
- Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Rishad J Dalal
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Mckenna G Hanson
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Joseph K Hexum
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Theresa M Reineke
- Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
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15
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Abbasi S, Uchida S. Multifunctional Immunoadjuvants for Use in Minimalist Nucleic Acid Vaccines. Pharmaceutics 2021; 13:644. [PMID: 34062771 PMCID: PMC8147386 DOI: 10.3390/pharmaceutics13050644] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/25/2021] [Accepted: 04/27/2021] [Indexed: 12/13/2022] Open
Abstract
Subunit vaccines based on antigen-encoding nucleic acids have shown great promise for antigen-specific immunization against cancer and infectious diseases. Vaccines require immunostimulatory adjuvants to activate the innate immune system and trigger specific adaptive immune responses. However, the incorporation of immunoadjuvants into nonviral nucleic acid delivery systems often results in fairly complex structures that are difficult to mass-produce and characterize. In recent years, minimalist approaches have emerged to reduce the number of components used in vaccines. In these approaches, delivery materials, such as lipids and polymers, and/or pDNA/mRNA are designed to simultaneously possess several functionalities of immunostimulatory adjuvants. Such multifunctional immunoadjuvants encode antigens, encapsulate nucleic acids, and control their pharmacokinetic or cellular fate. Herein, we review a diverse class of multifunctional immunoadjuvants in nucleic acid subunit vaccines and provide a detailed description of their mechanisms of adjuvanticity and induction of specific immune responses.
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Affiliation(s)
- Saed Abbasi
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Satoshi Uchida
- Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
- Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan
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16
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Bella Á, Di Trani CA, Fernández-Sendin M, Arrizabalaga L, Cirella A, Teijeira Á, Medina-Echeverz J, Melero I, Berraondo P, Aranda F. Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications. Cancers (Basel) 2021; 13:cancers13050963. [PMID: 33669017 PMCID: PMC7956655 DOI: 10.3390/cancers13050963] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/19/2021] [Accepted: 02/20/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Peritoneal carcinomatosis mouse models as a platform to test, improve and/or predict the appropriate therapeutic interventions in patients are crucial to providing medical advances. Here, we overview reported mouse models to explore peritoneal carcinomatosis in translational biomedical research. Abstract Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents.
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Affiliation(s)
- Ángela Bella
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Claudia Augusta Di Trani
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Myriam Fernández-Sendin
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Leire Arrizabalaga
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Assunta Cirella
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | - Álvaro Teijeira
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
| | | | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence: (P.B.); (F.A.)
| | - Fernando Aranda
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain; (Á.B.); (C.A.D.T.); (M.F.-S.); (L.A.); (A.C.); (Á.T.); (I.M.)
- Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain
- Correspondence: (P.B.); (F.A.)
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17
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Thakur N, Thakur S, Chatterjee S, Das J, Sil PC. Nanoparticles as Smart Carriers for Enhanced Cancer Immunotherapy. Front Chem 2020; 8:597806. [PMID: 33409265 PMCID: PMC7779678 DOI: 10.3389/fchem.2020.597806] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 11/30/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy for the treatment of many forms of cancer by stimulating body's own immune system. This therapy not only eradicates tumor cells by inducing strong anti-tumor immune response but also prevent their recurrence. The clinical cancer immunotherapy faces some insurmountable challenges including high immune-mediated toxicity, lack of effective and targeted delivery of cancer antigens to immune cells and off-target side effects. However, nanotechnology offers some solutions to overcome those limitations, and thus can potentiate the efficacy of immunotherapy. This review focuses on the advancement of nanoparticle-mediated delivery of immunostimulating agents for efficient cancer immunotherapy. Here we have outlined the use of the immunostimulatory nanoparticles as a smart carrier for effective delivery of cancer antigens and adjuvants, type of interactions between nanoparticles and the antigen/adjuvant as well as the factors controlling the interaction between nanoparticles and the receptors on antigen presenting cells. Besides, the role of nanoparticles in targeting/activating immune cells and modulating the immunosuppressive tumor microenvironment has also been discussed extensively. Finally, we have summarized some theranostic applications of the immunomodulatory nanomaterials in treating cancers based on the earlier published reports.
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Affiliation(s)
- Neelam Thakur
- Himalayan Centre for Excellence in Nanotechnology, Shoolini University, Solan, India
- School of Advanced Chemical Sciences, Faculty of Basic Sciences, Shoolini University, Solan, India
| | - Saloni Thakur
- Himalayan Centre for Excellence in Nanotechnology, Shoolini University, Solan, India
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, India
| | | | - Joydeep Das
- Himalayan Centre for Excellence in Nanotechnology, Shoolini University, Solan, India
- School of Advanced Chemical Sciences, Faculty of Basic Sciences, Shoolini University, Solan, India
| | - Parames C. Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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18
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Juneja R, Vadarevu H, Halman J, Tarannum M, Rackley L, Dobbs J, Marquez J, Chandler M, Afonin K, Vivero-Escoto JL. Combination of Nucleic Acid and Mesoporous Silica Nanoparticles: Optimization and Therapeutic Performance In Vitro. ACS APPLIED MATERIALS & INTERFACES 2020; 12:38873-38886. [PMID: 32805923 PMCID: PMC7748385 DOI: 10.1021/acsami.0c07106] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Programmable nucleic acid nanoparticles (NANPs) with precisely controlled functional compositions can regulate the conditional activation of various biological pathways and responses in human cells. However, the intracellular delivery of NANPs alone is hindered by their susceptibility to nuclease activity and inefficient crossing of biological membranes. In this work, we optimized the internalization and therapeutic performance of several representative NANPs delivered with mesoporous silica nanoparticles (MSNPs) tailored for efficient electrostatic association with NANPs. We compared the immunostimulatory properties of different NA-MS-NP complexes formed with globular, planar, and fibrous NANPs and demonstrated the maximum immunostimulation for globular NANPs. As a proof of concept, we assessed the specific gene silencing by NA-MS-NP complexes functionalized with siRNA targeting green fluorescent protein expressed in triple-negative human breast cancer cells. We showed that the fibrous NANPs have the highest silencing efficiency when compared to globular or planar counterparts. Finally, we confirmed the multimodal ability of MSNPs to co-deliver a chemotherapy drug, doxorubicin, and NANPs targeting apoptosis regulator gene BCL2 in triple-negative breast cancer and melanoma cell lines. Overall, the combination of NANPs and MSNPs may become a new promising approach to efficiently treat cancer and other diseases via the simultaneous targeting of various pathways.
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Affiliation(s)
- Ridhima Juneja
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Hemapriyadarshini Vadarevu
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- Nanoscale Science Program, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Justin Halman
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- Nanoscale Science Program, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Mubin Tarannum
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- Nanoscale Science Program, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Lauren Rackley
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Jacob Dobbs
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Jose Marquez
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Morgan Chandler
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- Nanoscale Science Program, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Kirill Afonin
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- Nanoscale Science Program, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- The Center for Biomedical Engineering and Science, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
| | - Juan L Vivero-Escoto
- Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- Nanoscale Science Program, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
- The Center for Biomedical Engineering and Science, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
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19
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Adams SF, Grimm AJ, Chiang CLL, Mookerjee A, Flies D, Jean S, McCann GA, Michaux J, Pak H, Huber F, Neal C, Dangaj D, Bassani-Sternberg M, Rusakiewicz S, Facciabene A, Coukos G, Gimotty PA, Kandalaft LE. Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes. J Immunother Cancer 2020; 8:jitc-2020-000875. [PMID: 32817208 PMCID: PMC7430560 DOI: 10.1136/jitc-2020-000875] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2020] [Indexed: 12/13/2022] Open
Abstract
Background Novel therapeutic strategies in ovarian cancer (OC) are needed as the survival rate remains dismally low. Although dendritic cell-based cancer vaccines are effective in eliciting therapeutic responses, their complex and costly manufacturing process hampers their full clinical utility outside specialized clinics. Here, we describe a novel approach of generating a rapid and effective cancer vaccine using ascites-derived monocytes for treating OC. Methods Using the ID8 mouse ovarian tumor model and OC patient samples, we isolated ascites monocytes and evaluated them with flow cytometry, Luminex cytokine and chemokine array analysis, ex vivo cocultures with T cells, in vivo tumor challenge and T cell transfer experiments, RNA-sequencing and mass spectrometry. Results We demonstrated the feasibility of isolating ascites monocytes and restoring their ability to function as bona fide antigen-presenting cells (APCs) with Toll-like receptor (TLR) 4 lipopolysaccharide and TLR9 CpG-oligonucleotides, and a blocking antibody to interleukin-10 receptor (IL-10R Ab) in the ID8 model. The ascites monocytes were laden with tumor antigens at a steady state in vivo. After a short 48 hours activation, they upregulated maturation markers (CD80, CD86 and MHC class I) and demonstrated strong ex vivo T cell stimulatory potential and effectively suppressed tumor and malignant ascites in vivo. They also induced protective long-term T cell memory responses. To evaluate the translational potential of this approach, we isolated ascites monocytes from stage III/IV chemotherapy-naïve OC patients. Similarly, the human ascites monocytes presented tumor-associated antigens (TAAs), including MUC1, ERBB2, mesothelin, MAGE, PRAME, GPC3, PMEL and TP53 at a steady state. After a 48-hour treatment with TLR4 and IL-10R Ab, they efficiently stimulated oligoclonal tumor-associated lymphocytes (TALs) with strong reactivity against TAAs. Importantly, the activated ascites monocytes retained their ability to activate TALs in the presence of ascitic fluid. Conclusions Ascites monocytes are naturally loaded with tumor antigen and can perform as potent APCs following short ex vivo activation. This novel ascites APC vaccine can be rapidly prepared in 48 hours with a straightforward and affordable manufacturing process, and would be an attractive therapeutic vaccine for OC.
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Affiliation(s)
- Sarah F Adams
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Division of Gynecologic Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA
| | - Alizée J Grimm
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Cheryl L-L Chiang
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Ananda Mookerjee
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dallas Flies
- Division of Gynecologic Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA
| | - Stephanie Jean
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Georgia A McCann
- Division of Gynecologic Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Justine Michaux
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - HuiSong Pak
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Florian Huber
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Christopher Neal
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Denarda Dangaj
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Michal Bassani-Sternberg
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Sylvie Rusakiewicz
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Andrea Facciabene
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - George Coukos
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, Lausanne, Switzerland
| | - Phyllis A Gimotty
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lana E Kandalaft
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland .,Ludwig Institute for Cancer Research, Lausanne, Switzerland
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20
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Wang C, Steinmetz NF. A Combination of Cowpea Mosaic Virus and Immune Checkpoint Therapy Synergistically Improves Therapeutic Efficacy in Three Tumor Models. ADVANCED FUNCTIONAL MATERIALS 2020; 30:2002299. [PMID: 34366758 PMCID: PMC8340625 DOI: 10.1002/adfm.202002299] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/30/2020] [Indexed: 05/20/2023]
Abstract
Immune checkpoint therapy (ICT) has the potential to treat cancer by removing the immunosuppressive brakes on T cell activity. However, ICT benefits only a subset of patients because most tumors are "cold", with limited pre-infiltration of effector T cells, poor immunogenicity, and low-level expression of checkpoint regulators. It has been previously reported that Cowpea mosaic virus (CPMV) promotes the activation of multiple innate immune cells and the secretion of pro-inflammatory cytokines to induce T cell cytotoxicity, suggesting that immunostimulatory CPMV could potentiate ICT. Here it is shown that in situ vaccination with CPMV increases the expression of checkpoint regulators on Foxp3-CD4+ effector T cells in the tumor microenvironment. It is shown that combined treatment with CPMV and selected checkpoint-targeting antibodies, specifically anti-PD-1 antibodies, or agonistic OX40-specific antibodies, reduced tumor burden, prolonged survival, and induced tumor antigen-specific immunologic memory to prevent relapse in three immunocompetent syngeneic mouse tumor models. This study therefore reveals new design principles for plant virus nanoparticles as novel immunotherapeutic adjuvants to elicit robust immune responses against cancer.
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Affiliation(s)
- Chao Wang
- Department of NanoEngineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Nicole F Steinmetz
- Department of NanoEngineering, Bioengineering, Radiology, Moores Cancer Center, Center for Nano-Immunoengineering, University of California San Diego, La Jolla, CA 92093, USA
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21
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Van Herck S, De Geest BG. Nanomedicine-mediated alteration of the pharmacokinetic profile of small molecule cancer immunotherapeutics. Acta Pharmacol Sin 2020; 41:881-894. [PMID: 32451411 PMCID: PMC7471422 DOI: 10.1038/s41401-020-0425-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/20/2020] [Indexed: 12/21/2022]
Abstract
The advent of immunotherapy is a game changer in cancer therapy with monoclonal antibody- and T cell-based therapeutics being the current flagships. Small molecule immunotherapeutics might offer advantages over the biological drugs in terms of complexity, tissue penetration, manufacturing cost, stability, and shelf life. However, small molecule drugs are prone to rapid systemic distribution, which might induce severe off-target side effects. Nanotechnology could aid in the formulation of the drug molecules to improve their delivery to specific immune cell subsets. In this review we summarize the current efforts in changing the pharmacokinetic profile of small molecule immunotherapeutics with a strong focus on Toll-like receptor agonists. In addition, we give our vision on limitations and future pathways in the route of nanomedicine to the clinical practice.
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Affiliation(s)
- Simon Van Herck
- Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium
| | - Bruno G De Geest
- Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.
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22
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Lemos H, Mohamed E, Ou R, McCardle C, Zheng X, McGuire K, Homer NZM, Mole DJ, Huang L, Mellor AL. Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis. Front Immunol 2020; 11:1256. [PMID: 32625215 PMCID: PMC7311583 DOI: 10.3389/fimmu.2020.01256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022] Open
Abstract
Reinforcing defective tolerogenic processes slows progression of autoimmune (AI) diseases and has potential to promote drug-free disease remission. Previously, we reported that DNA nanoparticles (DNPs) and cyclic dinucleotides (CDNs) slow progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, by activating the Stimulator of Interferon Genes (STING) signaling adaptor to stimulate interferon type 1 (IFN-I) production, which induced dendritic cells to express indoleamine 2,3 dioxygenase (IDO) and acquire immune regulatory phenotypes. Here, we show that therapeutic responses to DNPs depend on DNA sensing via cyclic GAMP synthase (cGAS) and interactions between Programmed Death-1 (PD-1) and PD-1 ligands. To investigate how increased tryptophan (Trp) metabolism by IDO promotes therapeutic responses mice were co-treated at EAE onset with DNPs and drugs that inhibit kynurenine aminotransferase-II (KatII) or 3-hydroxyanthranilic acid dioxygenase (HAAO) activity downstream of IDO in the kynurenine (Kyn) pathway. DNP and KatII or HAAO inhibitor co-treatments suppressed EAE progression more effectively than DNPs, while KatII inhibition had no significant therapeutic benefit and HAAO inhibition attenuated but did not prevent EAE progression. Moreover, therapeutic responses to co-treatments were durable as EAE progression did not resume after co-treatment. Thus, using STING agonists to boost IDO activity and manipulating the Kyn pathway downstream of IDO is an effective strategy to enhance tolerogenic responses that overcome autoimmunity to suppress EAE progression.
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MESH Headings
- Animals
- Antigen-Presenting Cells/drug effects
- Antigen-Presenting Cells/immunology
- Antigen-Presenting Cells/metabolism
- Autoimmunity
- B7-H1 Antigen/metabolism
- Chromatography, Liquid
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/drug therapy
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Enzyme Activation/drug effects
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Kynurenine/metabolism
- Membrane Proteins/agonists
- Metabolic Networks and Pathways
- Metabolome
- Metabolomics/methods
- Mice
- Mice, Knockout
- Nanoparticles
- Programmed Cell Death 1 Receptor/metabolism
- Signal Transduction/drug effects
- Tandem Mass Spectrometry
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Affiliation(s)
- Henrique Lemos
- Immune Metabolism Laboratory, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Eslam Mohamed
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Rong Ou
- Immune Metabolism Laboratory, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Caroline McCardle
- Immune Metabolism Laboratory, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Xiaozhong Zheng
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Kris McGuire
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Natalie Z. M. Homer
- Mass Spectrometry Core, Edinburgh Clinical Research Facility, Centre for Cardiovascular Sciences, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - Damian J. Mole
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Lei Huang
- Immune Metabolism Laboratory, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Andrew L. Mellor
- Immune Metabolism Laboratory, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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23
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Lin YX, Wang Y, Blake S, Yu M, Mei L, Wang H, Shi J. RNA Nanotechnology-Mediated Cancer Immunotherapy. Theranostics 2020; 10:281-299. [PMID: 31903120 PMCID: PMC6929632 DOI: 10.7150/thno.35568] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/06/2019] [Indexed: 12/19/2022] Open
Abstract
RNA molecules (e.g., siRNA, microRNA, and mRNA) have shown tremendous potential for immunomodulation and cancer immunotherapy. They can activate both innate and adaptive immune system responses by silencing or upregulating immune-relevant genes. In addition, mRNA-based vaccines have recently been actively pursued and tested in cancer patients, as a form of treatment. Meanwhile, various nanomaterials have been developed to enhance RNA delivery to the tumor and immune cells. In this review article, we summarize recent advances in the development of RNA-based therapeutics and their applications in cancer immunotherapy. We also highlight the variety of nanoparticle platforms that have been used for RNA delivery to elicit anti-tumor immune responses. Finally, we provide our perspectives of potential challenges and opportunities of RNA-based nanotherapeutics in clinical translation towards cancer immunotherapy.
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Affiliation(s)
- Yao-Xin Lin
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yi Wang
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Sara Blake
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Tufts University, Medford, MA 02155, USA
| | - Mian Yu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Lin Mei
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong 510006, China
| | - Hao Wang
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jinjun Shi
- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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24
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Dendritic Cells Loaded with Heat Shock-Conditioned Ovarian Epithelial Carcinoma Cell Lysates Elicit T Cell-Dependent Antitumor Immune Responses In Vitro. J Immunol Res 2019; 2019:9631515. [PMID: 31886313 PMCID: PMC6899292 DOI: 10.1155/2019/9631515] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 09/08/2019] [Accepted: 10/16/2019] [Indexed: 12/13/2022] Open
Abstract
Ovarian epithelial carcinoma (OEC) is the most frequent ovarian tumor, characterized by a high mortality in advanced stages where conventional therapies are not effective. Based on the role of the immune system in the progression of this disease, immunotherapy using checkpoint blockade has been considered as a therapeutic alternative. Nevertheless, its results do not match up to the positive results in entities like melanoma and other malignancies, suggesting the need to find other therapies to be used alone or in combination. Dendritic cell- (DC-) based vaccines have shown promising results in several types of cancer, such as melanoma, prostate, and lung cancers, due to the essential role played by DCs in the activation of specific T cells, thus using other ways of activating the immune response than immune checkpoint blockade. During the last decade, we have used DC-based vaccines loaded with an allogeneic heat shock-conditioned melanoma cell lysate in the treatment of advanced stage patients in a series of clinical trials. In these studies, 60% of treated patients showed immunological responses which correlated positively with improved survival. Considering the relevance of ovarian cancer and the promising results of our DC-based vaccine, we show here that heat shock-conditioned cell lysates derived from ovarian epithelial carcinoma cell lines have the potential to induce the phenotypic and functional maturation of human DC, which in turn, is able to induce an efficient CD4+ and CD8+ T cell-mediated immune responses against ovarian cancer cell lines in vitro. In summary, OEC heat shock-conditioned cell lysate-loaded DCs may be considered for future combined immunotherapy approaches against ovarian tumors.
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25
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Corradetti B, Pisano S, Conlan RS, Ferrari M. Nanotechnology and Immunotherapy in Ovarian Cancer: Tracing New Landscapes. J Pharmacol Exp Ther 2019; 370:636-646. [PMID: 30737357 PMCID: PMC6806629 DOI: 10.1124/jpet.118.254979] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 01/28/2019] [Indexed: 12/21/2022] Open
Abstract
Ovarian cancer (OC) is the seventh most common cancer in women worldwide. Standard therapeutic treatments involve debulking surgery combined with platinum-based chemotherapies. Of the patients with advanced-stage cancer who initially respond to current treatments, 50%-75% relapse. Immunotherapy-based approaches aimed at boosting antitumor immunity have recently emerged as promising tools to challenge tumor progression. Treatments with inhibitors of immune checkpoint molecules have shown impressive results in other types of tumors. However, only 15% of checkpoint inhibitors evaluated have proven successful in OC due to the immunosuppressive environment of the tumor and the transport barriers. This limits the efficacy of the existing immunotherapies. Nanotechnology-based delivery systems hold the potential to overcome such limitations. Various nanoformulations including polymeric, liposomes, and lipid-polymer hybrid nanoparticles have already been proposed to improve the biodistribution and targeting capabilities of drugs against tumor-associated immune cells, including dendritic cells and macrophages. In this review, we examine the impact of immunotherapeutic approaches that are currently under consideration for the treatment of OC. In this review, we also provide a comprehensive analysis of the existing nanoparticle-based synthetic strategies and their limitations and advantages over standard treatments. Furthermore, we discuss how the strength of the combination of nanotechnology with immunotherapy may help to overcome the current therapeutic limitations associated with their individual application and unravel a new paradigm in the treatment of this malignancy.
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Affiliation(s)
- Bruna Corradetti
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas (B.C., S.P., R.S.C., M.F.); Swansea University Medical School, Singleton Park, Swansea, United Kingdom (B.C., S.P., R.S.C.); and Department of Medicine, Weill Cornell Medical College, New York, New York (M.F.)
| | - Simone Pisano
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas (B.C., S.P., R.S.C., M.F.); Swansea University Medical School, Singleton Park, Swansea, United Kingdom (B.C., S.P., R.S.C.); and Department of Medicine, Weill Cornell Medical College, New York, New York (M.F.)
| | - Robert Steven Conlan
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas (B.C., S.P., R.S.C., M.F.); Swansea University Medical School, Singleton Park, Swansea, United Kingdom (B.C., S.P., R.S.C.); and Department of Medicine, Weill Cornell Medical College, New York, New York (M.F.)
| | - Mauro Ferrari
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas (B.C., S.P., R.S.C., M.F.); Swansea University Medical School, Singleton Park, Swansea, United Kingdom (B.C., S.P., R.S.C.); and Department of Medicine, Weill Cornell Medical College, New York, New York (M.F.)
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26
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Wu Y, Chen W, Xu ZP, Gu W. PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Front Immunol 2019; 10:2022. [PMID: 31507611 PMCID: PMC6718566 DOI: 10.3389/fimmu.2019.02022] [Citation(s) in RCA: 291] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 08/09/2019] [Indexed: 12/31/2022] Open
Abstract
Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.
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Affiliation(s)
| | | | | | - Wenyi Gu
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, QLD, Australia
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27
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Oakes RS, Froimchuk E, Jewell CM. Engineering Biomaterials to Direct Innate Immunity. ADVANCED THERAPEUTICS 2019; 2:1800157. [PMID: 31236439 PMCID: PMC6590522 DOI: 10.1002/adtp.201800157] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Indexed: 12/18/2022]
Abstract
Small alterations during early stages of innate immune response can drive large changes in how adaptive immune cells develop and function during protective immunity or disease. Controlling these events creates exciting potential in development of immune engineered vaccines and therapeutics. This progress report discusses recent biomaterial technologies exploiting innate immunity to dissect immune function and to design new vaccines and immunotherapies for infectious diseases, cancer, and autoimmunity. Across these examples, an important idea is the possibility to co-opt innate immune mechanisms to enhance immunity during infection and cancer. During inflammatory or autoimmune disease, some of these same innate immune mechanisms can be manipulated in different ways to control excess inflammation by promotion of immunological tolerance.
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Affiliation(s)
- R. S. Oakes
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - E. Froimchuk
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, 20742, USA
| | - C. M. Jewell
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, 20742, USA
- United States Department of Veterans Affairs, VA Maryland Health Care System, 10. N Green Street, Baltimore, Maryland 21201, USA
- Department of Microbiology and Immunology, University of Maryland Medical School, 685 West Baltimore Street, HSF-I Suite 380, Baltimore, MD, 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA
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Toll-Like Receptors as Therapeutic Targets in Central Nervous System Tumors. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5286358. [PMID: 31240216 PMCID: PMC6556293 DOI: 10.1155/2019/5286358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 05/08/2019] [Indexed: 12/24/2022]
Abstract
In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of central nervous system (CNS) tumors. However, improvements in risk classification, prognosis, and treatment have not been sufficient. Currently, great importance has been placed to the tumor microenvironment and the immune system, which are very important components that influence the establishment and development of tumors. Toll-like receptors (TLRs) are innate immunite system sensors of a wide variety of molecules, such as those associated with microorganisms and danger signals. TLRs are expressed on many cells, including immune cells and nonimmune cells such as neurons and cancer cells. In the tumor microenvironment, activation of TLRs plays dual antitumoral (dendritic cells, cytotoxic T cells, and natural killer cells activation) and protumoral effects (tumor cell proliferation, survival, and resistance to chemotherapy) and constitutes an area of opportunities and challenges in the development of new therapeutic strategies. Several clinical trials have been carried out, and others are currently in process; however, the results obtained to date have been contradictory and have not led to a definitive position about the use of TLR agonists in adjuvant therapy during the treatment of central nervous system (CNS) tumors. In this review, we focus on recent advances in TLR agonists as immunotherapies for treatment of CNS tumors.
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Zhang G, Liu C, Bai H, Cao G, Cui R, Zhang Z. Combinatorial therapy of immune checkpoint and cancer pathways provides a novel perspective on ovarian cancer treatment. Oncol Lett 2019; 17:2583-2591. [PMID: 30854033 DOI: 10.3892/ol.2019.9902] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 11/21/2018] [Indexed: 12/14/2022] Open
Abstract
An increasing number of studies have reported that immunotherapy serves a significant role in ovarian cancer treatment. In recent years, blockade of checkpoint pathways, including programmed death-ligand 1 (PD-L1)/programmed death-1 and cytotoxic T-lymphocyte-associated protein 4, has demonstrated significant clinical and preclinical benefits in the treatment of ovarian cancer. Additionally, tumor-associated angiogenesis and homologous recombination deficiency frequently occurs in patients with high-grade ovarian cancer, which makes cancer cells more susceptible to targeted therapies, including therapies targeting poly (ADP-ribose) polymerase inhibitor, and anti-angiogenic approaches. Additionally, targeted therapy has been associated with elevated PD-L1 expression in tumor cells, increased T-cell infiltration in tumors and dendritic cell stimulation. This synergistic effect provides the rationale for the joint application of targeted therapy and immunotherapy. Checkpoint blockades are able to elicit durable antitumor immune reactions and complement the transient antitumor effect of targeted therapies. The current review discusses the underlying mechanism of these therapies and novel developments in combined therapy for the treatment of ovarian cancer.
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Affiliation(s)
- Guyu Zhang
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10000, P.R. China
| | - Chongdong Liu
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10000, P.R. China
| | - Huiming Bai
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10000, P.R. China
| | - Guangming Cao
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10000, P.R. China
| | - Ran Cui
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10000, P.R. China
| | - Zhengyu Zhang
- Department of Gynecology and Obstetrics, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10000, P.R. China
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30
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Martin Lluesma S, Graciotti M, Chiang CLL, Kandalaft LE. Does the Immunocompetent Status of Cancer Patients Have an Impact on Therapeutic DC Vaccination Strategies? Vaccines (Basel) 2018; 6:E79. [PMID: 30477198 PMCID: PMC6313858 DOI: 10.3390/vaccines6040079] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/09/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022] Open
Abstract
Although different types of therapeutic vaccines against established cancerous lesions in various indications have been developed since the 1990s, their clinical benefit is still very limited. This observed lack of effectiveness in cancer eradication may be partially due to the often deficient immunocompetent status of cancer patients, which may facilitate tumor development by different mechanisms, including immune evasion. The most frequently used cellular vehicle in clinical trials are dendritic cells (DCs), thanks to their crucial role in initiating and directing immune responses. Viable vaccination options using DCs are available, with a positive toxicity profile. For these reasons, despite their limited therapeutic outcomes, DC vaccination is currently considered an additional immunotherapeutic option that still needs to be further explored. In this review, we propose potential actions aimed at improving DC vaccine efficacy by counteracting the detrimental mechanisms recognized to date and implicated in establishing a poor immunocompetent status in cancer patients.
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Affiliation(s)
- Silvia Martin Lluesma
- Center of Experimental Therapeutics, Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland.
| | - Michele Graciotti
- Vaccine development laboratory, Ludwig Center for Cancer Research, Lausanne 1011, Switzerland.
| | - Cheryl Lai-Lai Chiang
- Vaccine development laboratory, Ludwig Center for Cancer Research, Lausanne 1011, Switzerland.
| | - Lana E Kandalaft
- Center of Experimental Therapeutics, Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland.
- Vaccine development laboratory, Ludwig Center for Cancer Research, Lausanne 1011, Switzerland.
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31
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McCloskey CW, Rodriguez GM, Galpin KJC, Vanderhyden BC. Ovarian Cancer Immunotherapy: Preclinical Models and Emerging Therapeutics. Cancers (Basel) 2018; 10:cancers10080244. [PMID: 30049987 PMCID: PMC6115831 DOI: 10.3390/cancers10080244] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/20/2018] [Accepted: 07/23/2018] [Indexed: 12/16/2022] Open
Abstract
Immunotherapy has emerged as one of the most promising approaches for ovarian cancer treatment. The tumor microenvironment (TME) is a key factor to consider when stimulating antitumoral responses as it consists largely of tumor promoting immunosuppressive cell types that attenuate antitumor immunity. As our understanding of the determinants of the TME composition grows, we have begun to appreciate the need to address both inter- and intra-tumor heterogeneity, mutation/neoantigen burden, immune landscape, and stromal cell contributions. The majority of immunotherapy studies in ovarian cancer have been performed using the well-characterized murine ID8 ovarian carcinoma model. Numerous other animal models of ovarian cancer exist, but have been underutilized because of their narrow initial characterizations in this context. Here, we describe animal models that may be untapped resources for the immunotherapy field because of their shared genomic alterations and histopathology with human ovarian cancer. We also shed light on the strengths and limitations of these models, and the knowledge gaps that need to be addressed to enhance the utility of preclinical models for testing novel immunotherapeutic approaches.
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Affiliation(s)
- Curtis W McCloskey
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
| | - Galaxia M Rodriguez
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
| | - Kristianne J C Galpin
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
| | - Barbara C Vanderhyden
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
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Harrison EB, Azam SH, Pecot CV. Targeting Accessories to the Crime: Nanoparticle Nucleic Acid Delivery to the Tumor Microenvironment. Front Pharmacol 2018; 9:307. [PMID: 29670528 PMCID: PMC5893903 DOI: 10.3389/fphar.2018.00307] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 03/16/2018] [Indexed: 12/18/2022] Open
Abstract
Nucleic acid delivery for cancer holds extraordinary promise. Increasing expression of tumor suppressor genes or inhibition of oncogenes in cancer cells has important therapeutic potential. However, several barriers impair progress in cancer gene delivery. These include effective delivery to cancer cells and relevant intracellular compartments. Although viral gene delivery can be effective, it has the disadvantages of being immuno-stimulatory, potentially mutagenic and lacking temporal control. Various nanoparticle (NP) platforms have been developed to overcome nucleic acid delivery hurdles, but several challenges still exist. One such challenge has been the accumulation of NPs in non-cancer cells within the tumor microenvironment (TME) as well as the circulation. While uptake by these cancer-associated cells is considered to be an off-target effect in some contexts, several strategies have now emerged to utilize NP-mediated gene delivery to intentionally alter the TME. For example, the similarity of NPs in shape and size to pathogens promotes uptake by antigen presenting cells, which can be used to increase immune stimulation and promote tumor killing by T-lymphocytes. In the era of immunotherapy, boosting the ability of the immune system to eliminate cancer cells has proven to be an exciting new area in cancer nanotechnology. Given the importance of cancer-associated cells in tumor growth and metastasis, targeting these cells in the TME opens up new therapeutic applications for NPs. This review will cover evidence for non-cancer cell accumulation of NPs in animal models and patients, summarize characteristics that promote NP delivery to different cell types, and describe several therapeutic strategies for gene modification within the TME.
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Affiliation(s)
- Emily B. Harrison
- Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Salma H. Azam
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Chad V. Pecot
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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33
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Sau S, Alsaab HO, Bhise K, Alzhrani R, Nabil G, Iyer AK. Multifunctional nanoparticles for cancer immunotherapy: A groundbreaking approach for reprogramming malfunctioned tumor environment. J Control Release 2018; 274:24-34. [PMID: 29391232 PMCID: PMC5847475 DOI: 10.1016/j.jconrel.2018.01.028] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 01/24/2018] [Accepted: 01/26/2018] [Indexed: 12/24/2022]
Abstract
Several cancer immunotherapy approaches have been recently introduced into the clinics and they have shown remarkable therapeutic potentials. The groundbreaking cancer immunotherapeutic agents function as a stimulant or modulator of the body immune system to fight against or kill cancers. Although targeted immunotherapies such as immune check point inhibitors (CTLA-4 or PD-1/PD-L1), DNA vaccination and CAR-T therapy are revolutionizing cancer treatment, the delivery efficacy can be further improved while their off-target toxicity can be mitigated through nanotechnology approaches. Recent research has demonstrated that nanotechnology has multifaceted role for (i) reeducating tumor associated macrophages (TAM) to function as tumor suppressor agent, (ii) serving as an efficient alternative for Chimeric Antigen Receptor (CAR)-T cell generation and transduction, and (iii) selective knockdown of Kras oncogene addiction by nano-Crisper-Cas9 delivery system. The function of host immune stimulatory signals and tumor immunotherapies can further be improved by repurposing of nanomedicine platform. This review summarizes the role of multifunctional polymeric, lipid, metallic and cell based nanoparticles for improving current immunotherapy.
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Affiliation(s)
- Samaresh Sau
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA.
| | - Hashem O Alsaab
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA; Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 26571, Saudi Arabia
| | - Ketki Bhise
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA
| | - Rami Alzhrani
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA; Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 26571, Saudi Arabia
| | - Ghazal Nabil
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA; Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, 259 Mack Ave, Wayne State University, Detroit, MI 48201, USA; Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
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34
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BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep 2017; 16:2829-2837. [PMID: 27626654 DOI: 10.1016/j.celrep.2016.08.032] [Citation(s) in RCA: 327] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 07/21/2016] [Accepted: 08/10/2016] [Indexed: 12/14/2022] Open
Abstract
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression.
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35
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Kwak G, Kim D, Nam GH, Wang SY, Kim IS, Kim SH, Kwon IC, Yeo Y. Programmed Cell Death Protein Ligand-1 Silencing with Polyethylenimine-Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth. ACS NANO 2017; 11:10135-10146. [PMID: 28985469 PMCID: PMC5697980 DOI: 10.1021/acsnano.7b04717] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Programmed cell death protein-1 (PD-1) is a prominent immune checkpoint receptor interacting with its ligand, programmed cell death protein ligand-1 (PD-L1, B7-H1). The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and, thus, interferes with antitumor T-cell immunity. In addition, PD-1/PD-L1 interaction promotes tumorigenesis via the mTOR signaling pathway in a group of cancers including melanoma. Based on the dual functions of PD-1/PD-L1 interactions in tumor progression, we hypothesize that siRNA targeting PD-L1 (siPD-L1) will suppress melanoma growth, acting on both immune checkpoint and intrinsic tumorigenesis pathways. We tested this hypothesis by delivering siPD-L1 with a polymeric carrier ("pd") consisting of disulfide-cross-linked polyethylenimine (CLPEI) and dermatan sulfate (DS), which we previously found to have a specific interaction with CD146-positive B16F10 melanoma cells. The siPD-L1/pd suppressed the expression of PD-L1 in the interferon-γ (IFN-γ)-challenged B16F10 melanoma cells in a cell-type dependent manner and attenuated the expression of tumor-specific genes in B16F10 cells. siPD-L1/pd suppressed the B16F10 melanoma growth in C57BL/6 immune-competent mice with increased tumor-specific immunity. siPD-L1/pd also suppressed melanoma growth in immune-compromised nude mice. Both animals showed a positive correlation between PD-L1 and p-S6k (a marker of mTOR pathway activation) expression in tumors. These results indicate that the siPD-L1/pd complex attenuates melanoma growth in both T-cell-dependent and independent mechanisms.
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Affiliation(s)
- Gijung Kwak
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Dongkyu Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Gi-hoon Nam
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Sun Young Wang
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - In-San Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Sun Hwa Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Ick-Chan Kwon
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Yoon Yeo
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
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Stephen TL, Payne KK, Chaurio RA, Allegrezza MJ, Zhu H, Perez-Sanz J, Perales-Puchalt A, Nguyen JM, Vara-Ailor AE, Eruslanov EB, Borowsky ME, Zhang R, Laufer TM, Conejo-Garcia JR. SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells. Immunity 2017; 46:51-64. [PMID: 28099864 DOI: 10.1016/j.immuni.2016.12.015] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/07/2016] [Accepted: 12/06/2016] [Indexed: 12/16/2022]
Abstract
Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor β (Tgf-β) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.
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Affiliation(s)
- Tom L Stephen
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Kyle K Payne
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Ricardo A Chaurio
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Michael J Allegrezza
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Hengrui Zhu
- Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Jairo Perez-Sanz
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Alfredo Perales-Puchalt
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Jenny M Nguyen
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Ana E Vara-Ailor
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Evgeniy B Eruslanov
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mark E Borowsky
- Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA
| | - Rugang Zhang
- Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Terri M Laufer
- Department of Rheumatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jose R Conejo-Garcia
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
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Shen C, Li J, Zhang Y, Li Y, Shen G, Zhu J, Tao J. Polyethylenimine-based micro/nanoparticles as vaccine adjuvants. Int J Nanomedicine 2017; 12:5443-5460. [PMID: 28814862 PMCID: PMC5546778 DOI: 10.2147/ijn.s137980] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Vaccines have shown great success in treating and preventing tumors and infections, while adjuvants are always demanded to ensure potent immune responses. Polyethylenimine (PEI), as one of the well-studied cationic polymers, has been used as a transfection reagent for decades. However, increasing evidence has shown that PEI-based particles are also capable of acting as adjuvants. In this paper, we briefly review the physicochemical properties and the broad applications of PEI in different fields, and elaborate on the intracellular processes of PEI-based vaccines. In addition, we sum up the proof of their in vivo and clinical applications. We also highlight some mechanisms proposed for the intrinsic immunoactivation function of PEI, followed by the challenges and future perspectives of the applications of PEI in the vaccines, as well as some strategies to elicit the desirable immune responses.
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Affiliation(s)
- Chen Shen
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Li
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Zhang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuce Li
- School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, China
| | - Guanxin Shen
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jintao Zhu
- School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Tao
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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38
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Affiliation(s)
- Steven Fiering
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA
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39
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Kim BK, Kim D, Kwak G, Yhee JY, Kwon IC, Kim SH, Yeo Y. Polyethylenimine-dermatan sulfate complex, a bioactive biomaterial with unique toxicity to CD146-positive cancer cells. ACS Biomater Sci Eng 2017; 3:990-999. [PMID: 29457127 DOI: 10.1021/acsbiomaterials.7b00207] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We report unique bioactivity of a polycation-polyanion complex with potential utility for cancer therapy. A complex of disulfide-crosslinked polyethyleneimine (CLPEI), a polycation used for gene complexation, and dermatan sulfate (DS), an anionic polysaccharide to shield excessive cationic charge of the former, has toxicity to a specific group of cancer cell lines, including B16-F10 murine melanoma, A375SM human melanoma, and PC-3 human prostate cancer cells. These CLPEI-DS-sensitive cells express CD146, which binds to the complex via interaction with DS. There is a positive correlation between toxicity and intracellular level of CLPEI, indicating that the CLPEI-DS-sensitivity is attributable to the increased cellular uptake of CLPEI mediated by the DS-CD146 interactions. In vitro studies show that CLPEI-DS complex causes G0/G1 phase arrest and apoptotic cell death. In syngeneic and allograft models of B16-F10 melanoma, CLPEI-DS complex administered with a sub-toxic level of doxorubicin potentiates the chemotherapeutic effect of the drug by loosening tumor tissues. Given the unique toxicity, CLPEI-DS complex may be a useful carrier of gene or chemotherapeutics for the therapy of CD146-positive cancers.
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Affiliation(s)
- Bieong-Kil Kim
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Dongkyu Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Gijung Kwak
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.,KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Ji Young Yhee
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Ick-Chan Kwon
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Sun Hwa Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Yoon Yeo
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.,Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.,Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
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Hall A, Lächelt U, Bartek J, Wagner E, Moghimi SM. Polyplex Evolution: Understanding Biology, Optimizing Performance. Mol Ther 2017; 25:1476-1490. [PMID: 28274797 DOI: 10.1016/j.ymthe.2017.01.024] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/25/2017] [Accepted: 01/25/2017] [Indexed: 02/06/2023] Open
Abstract
Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants.
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Affiliation(s)
- Arnaldur Hall
- Genome Integrity Unit, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
| | - Ulrich Lächelt
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Nanosystems Initiative Munich, 80799 Munich, Germany
| | - Jiri Bartek
- Genome Integrity Unit, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, 171 65 Solna, Sweden
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Nanosystems Initiative Munich, 80799 Munich, Germany.
| | - Seyed Moein Moghimi
- School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees TS17 6BH, UK.
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Abstract
Many cancers including ovarian, pancreatic, colon, liver, and stomach cancers are largely confined to the peritoneal cavity. Peritoneal tumors are directly accessible by intraperitoneal injections. Previously we demonstrated that intraperitoneal injection of nanoparticles and subsequent ingestion by tumor-associated phagocytes can be used to either directly impact tumors or stimulate antitumor immune responses. Here we outline methods to specifically utilize iron oxide nanoparticles with the ID8-Defb29/Vegf-A murine ovarian cancer model and discuss the tendency of phagocytes to ingest nanoparticles and the potential of phagocytes to carry nanoparticles to tumors resulting in direct killing of tumor cells or stimulate antitumor immune responses in peritoneal cancers. This basic approach can be modified as needed for different types of tumors and nanoparticles.
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Affiliation(s)
- Mee Rie Sheen
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA
| | - Steven Fiering
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA.
- Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
- Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, 622 Rubin DHMC, Lebanon, NH, 03756, USA.
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Svoronos N, Perales-Puchalt A, Allegrezza MJ, Rutkowski MR, Payne KK, Tesone AJ, Nguyen JM, Curiel TJ, Cadungog MG, Singhal S, Eruslanov EB, Zhang P, Tchou J, Zhang R, Conejo-Garcia JR. Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells. Cancer Discov 2016; 7:72-85. [PMID: 27694385 DOI: 10.1158/2159-8290.cd-16-0502] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 09/28/2016] [Accepted: 09/28/2016] [Indexed: 01/08/2023]
Abstract
The role of estrogens in antitumor immunity remains poorly understood. Here, we show that estrogen signaling accelerates the progression of different estrogen-insensitive tumor models by contributing to deregulated myelopoiesis by both driving the mobilization of myeloid-derived suppressor cells (MDSC) and enhancing their intrinsic immunosuppressive activity in vivo Differences in tumor growth are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Therefore, estrogen signaling is a crucial mechanism underlying pathologic myelopoiesis in cancer. Our work suggests that new antiestrogen drugs that have no agonistic effects may have benefits in a wide range of cancers, independently of the expression of estrogen receptors in tumor cells, and may synergize with immunotherapies to significantly extend survival. SIGNIFICANCE Ablating estrogenic activity delays malignant progression independently of the tumor cell responsiveness, owing to a decrease in the mobilization and immunosuppressive activity of MDSCs, which boosts T-cell-dependent antitumor immunity. Our results provide a mechanistic rationale to block estrogen signaling with newer antagonists to boost the effectiveness of anticancer immunotherapies. Cancer Discov; 7(1); 72-85. ©2016 AACR.See related commentary by Welte et al., p. 17This article is highlighted in the In This Issue feature, p. 1.
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Affiliation(s)
- Nikolaos Svoronos
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Alfredo Perales-Puchalt
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Michael J Allegrezza
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Melanie R Rutkowski
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Kyle K Payne
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Amelia J Tesone
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Jenny M Nguyen
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Tyler J Curiel
- The Graduate School of Biomedical Sciences, The University of Texas Health Science Center, San Antonio, Texas.,Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas.,Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, Texas
| | - Mark G Cadungog
- Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware
| | - Sunil Singhal
- Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Evgeniy B Eruslanov
- Division of Thoracic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Paul Zhang
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Julia Tchou
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rugang Zhang
- Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Jose R Conejo-Garcia
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Batool M, Anwar MA, Choi S. Toll-like receptors targeting technology for the treatment of lymphoma. Expert Opin Drug Discov 2016; 11:1047-1059. [PMID: 27602749 DOI: 10.1080/17460441.2016.1233964] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION The crucial role of Toll-like Receptors (TLRs) in innate and adaptive immune systems is well discussed in the literature. In cancer, TLRs act as a double-edged sword that can promote or suppress tumor growth. Areas covered: In this article, the authors uncover the potential role of TLRs in lymphomas, which are cancers related to the lymphatic system and blood cells. TLRs are de facto inflammation-inducing receptors that can either worsen disease or ameliorate lymphoma treatment. From this perspective, the usage of TLRs to modulate the immune system toward lymphoma regression is desirable. Various strategies have been used so far, and novel ways are being sought out to cure lymphoma. Expert opinion: TLR ligands have successfully been used to improve patient health; however, these receptors must be finely tuned to further optimize therapy. For a better outcome, novel specific ligands, improved pharmacodynamics, and unique targets should be discerned. Ligands with conjugated molecules, nanoparticles, and targeted drug delivery can highly optimize the therapy for lymphoma with various etiologies.
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Affiliation(s)
- Maria Batool
- a Department of Molecular Science and Technology , Ajou University , Suwon , Korea
| | - Muhammad Ayaz Anwar
- a Department of Molecular Science and Technology , Ajou University , Suwon , Korea
| | - Sangdun Choi
- a Department of Molecular Science and Technology , Ajou University , Suwon , Korea
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Bernal L, Alvarado-Vázquez A, Ferreira DW, Paige CA, Ulecia-Morón C, Hill B, Caesar M, Romero-Sandoval EA. Evaluation of a nanotechnology-based approach to induce gene-expression in human THP-1 macrophages under inflammatory conditions. Immunobiology 2016; 222:399-408. [PMID: 27615510 DOI: 10.1016/j.imbio.2016.08.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 08/17/2016] [Accepted: 08/29/2016] [Indexed: 12/18/2022]
Abstract
Macrophages orchestrate the initiation and resolution of inflammation by producing pro- and anti-inflammatory products. An imbalance in these mediators may originate from a deficient or excessive immune response. Therefore, macrophages are valid therapeutic targets to restore homeostasis under inflammatory conditions. We hypothesize that a specific mannosylated nanoparticle effectively induces gene expression in human macrophages under inflammatory conditions without undesirable immunogenic responses. THP-1 macrophages were challenged with lipopolysaccharide (LPS, 5μg/mL). Polyethylenimine (PEI) nanoparticles grafted with a mannose receptor ligand (Man-PEI) were used as a gene delivery method. Nanoparticle toxicity, Man-PEI cellular uptake rate and gene induction efficiency (GFP, CD14 or CD68) were studied. Potential immunogenic responses were evaluated by measuring the production of tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-6 and IL-10. Man-PEI did not produce cytotoxicity, and it was effectively up-taken by THP-1 macrophages (69%). This approach produced a significant expression of GFP (mRNA and protein), CD14 and CD68 (mRNA), and transiently and mildly reduced IL-6 and IL-10 levels in LPS-challenged macrophages. Our results indicate that Man-PEI is suitable for inducing an efficient gene overexpression in human macrophages under inflammatory conditions with limited immunogenic responses. Our promising results set the foundation to test this technology to induce functional anti-inflammatory genes.
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Affiliation(s)
- Laura Bernal
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA; Department of Systems' Biology, School of Medicine, University of Alcala. Campus Universitario - C/ 19, Carretera Madrid-Barcelona, Km 33,600, 28871 Alcalá de Henares, Madrid, Spain.
| | - Abigail Alvarado-Vázquez
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA.
| | - David Wilson Ferreira
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA; Department of Pharmacology, Ribeirao Preto Medical School-University of Sao Paulo, 3900 Bandeirantes Ave., Ribeirão Preto, SP, 14049-900, Brazil.
| | - Candler A Paige
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA.
| | - Cristina Ulecia-Morón
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA; Department of Physiology, Anatomy and Cellular Biology, University Pablo de Olavide de Sevilla, Carretera de Utrera Km. 1, 41013, Sevilla, Spain.
| | - Bailey Hill
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA.
| | - Marina Caesar
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA.
| | - E Alfonso Romero-Sandoval
- Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, 307 N. Broad St, Clinton, SC 29325, USA.
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Lee SJ, Kim MJ, Kwon IC, Roberts TM. Delivery strategies and potential targets for siRNA in major cancer types. Adv Drug Deliv Rev 2016; 104:2-15. [PMID: 27259398 DOI: 10.1016/j.addr.2016.05.010] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 02/24/2016] [Accepted: 05/15/2016] [Indexed: 02/08/2023]
Abstract
Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types.
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46
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Perales-Puchalt A, Svoronos N, Rutkowski MR, Allegrezza MJ, Tesone AJ, Payne KK, Wickramasinghe J, Nguyen JM, O'Brien SW, Gumireddy K, Huang Q, Cadungog MG, Connolly DC, Tchou J, Curiel TJ, Conejo-Garcia JR. Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res 2016; 23:441-453. [PMID: 27435394 DOI: 10.1158/1078-0432.ccr-16-0492] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 07/11/2016] [Accepted: 07/12/2016] [Indexed: 01/08/2023]
Abstract
PURPOSE To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells. EXPERIMENTAL DESIGN FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells. RESULTS FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T cells away from targeted tumor cells. CONCLUSIONS T cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441-53. ©2016 AACR.
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Affiliation(s)
- Alfredo Perales-Puchalt
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Nikolaos Svoronos
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Melanie R Rutkowski
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Michael J Allegrezza
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Amelia J Tesone
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Kyle K Payne
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | | | - Jenny M Nguyen
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Shane W O'Brien
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Kiranmai Gumireddy
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Qihong Huang
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Mark G Cadungog
- Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware
| | - Denise C Connolly
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Julia Tchou
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Tyler J Curiel
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Jose R Conejo-Garcia
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Endogenous and tumour-derived microRNAs regulate cross-presentation in dendritic cells and consequently cytotoxic T cell function. Cytotechnology 2016; 68:2223-2233. [PMID: 27193424 DOI: 10.1007/s10616-016-9975-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/20/2016] [Indexed: 01/25/2023] Open
Abstract
Dendritic cells (DCs) are potent antigen presenting cells (APCs). They are also specialized in the induction of cytotoxic T lymphocyte mediated responses against extracellular antigens, including tumour-specific antigens, by presenting peptide-Major Histocompatibility Complex (MHC) I complexes to naïve CD8+ T cells in lymphoid tissues, a process called cross-presentation. Emerging evidence suggests that the efficiency of cross-presentation can be influenced by a unique set of microRNAs (miRNAs). Some are differentially expressed in the course of morphological and functional development of DCs while tumorigenic miRNAs (onco-miRs) can be delivered to and inserted into DCs via exosomes. The latter reprogram the miRNA repertoire of DCs, transforming them from effective APCs to negative modulators of immunity, ultimately aiding cancers to evade host immunity. On the other hand, endogenous microRNAs can influence cross-presentation either positively or negatively. In this review, we discuss the possible mechanisms by which specific miRNAs influence cross-presentation as well as the viability of manipulating the expression of miRNAs that regulate DC cross-presentation as a potential cancer immunotherapy intervention.
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48
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Foxley MA, Friedline AW, Jensen JM, Nimmo SL, Scull EM, King JB, Strange S, Xiao MT, Smith BE, Thomas Iii KJ, Glatzhofer DT, Cichewicz RH, Rice CV. Efficacy of ampicillin against methicillin-resistant Staphylococcus aureus restored through synergy with branched poly(ethylenimine). J Antibiot (Tokyo) 2016; 69:871-878. [PMID: 27189119 PMCID: PMC5115998 DOI: 10.1038/ja.2016.44] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 03/22/2016] [Accepted: 03/29/2016] [Indexed: 01/20/2023]
Abstract
Beta-lactam antibiotics kill Staphylococcus aureus bacteria by inhibiting the function of cell-wall penicillin binding proteins (PBPs) 1 and 3. However, β-lactams are ineffective against PBP2a, used by methicillin-resistant Staphylococcus aureus (MRSA) to perform essential cell wall crosslinking functions. PBP2a requires teichoic acid to properly locate and orient the enzyme, and thus MRSA is susceptible to antibiotics that prevent teichoic acid synthesis in the bacterial cytoplasm. As an alternative, we have used branched poly(ethylenimine), BPEI, to target teichoic acid in the bacterial cell wall. The result is restoration of MRSA susceptibility to the β-lactam antibiotic ampicillin with a MIC of 1 μg/mL, superior to that of vancomycin (MIC = 3.7 μg/mL). A checkerboard assay shows synergy of BPEI and ampicillin. Nuclear magnetic resonance (NMR) data show that BPEI alters the teichoic acid chemical environment. Laser scanning confocal microscopy (LSCM) images show BPEI residing on the bacterial cell wall where teichoic acids and PBPs are located.
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Affiliation(s)
- Melissa A Foxley
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Anthony W Friedline
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Jessica M Jensen
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Susan L Nimmo
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Erin M Scull
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Jarrod B King
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Stoffel Strange
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Min T Xiao
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Benjamin E Smith
- Samuel Roberts Noble Microscopy Laboratory, University of Oklahoma, Norman, OK, USA
| | - Kieth J Thomas Iii
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Daniel T Glatzhofer
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Robert H Cichewicz
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
| | - Charles V Rice
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA
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49
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Flies DB, Higuchi T, Harris JC, Jha V, Gimotty PA, Adams SF. Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103(+) dendritic cells in late-stage ovarian cancer. Oncoimmunology 2016; 5:e1185583. [PMID: 27622059 DOI: 10.1080/2162402x.2016.1185583] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 04/25/2016] [Accepted: 04/27/2016] [Indexed: 12/24/2022] Open
Abstract
Although immune infiltrates in ovarian cancer are associated with improved survival, the ovarian tumor environment has been characterized as immunosuppressive, due in part to functional shifts among dendritic cells with disease progression. We hypothesized that flux in dendritic cell subpopulations with cancer progression were responsible for observed differences in antitumor immune responses in early and late-stage disease. Here we identify three dendritic cell subsets with disparate functions in the ovarian tumor environment. CD11c+CD11b(-)CD103(+) dendritic cells are absent in the peritoneal cavity of healthy mice but comprise up to 40% of dendritic cells in tumor-bearing mice and retain T cell stimulatory capacity in advanced disease. Among CD11c+CD11b+ cells, Lair-1 expression distinguishes stimulatory and immunoregulatory DC subsets, which are also enriched in the tumor environment. Notably, PD-L1 is expressed by Lair-1(hi) immunoregulatory dendritic cells, and may contribute to local tumor antigen-specific T cell dysfunction. Using an adoptive transfer model, we find that PD-1 blockade enables tumor-associated CD103(+) dendritic cells to promote disease clearance. These data demonstrate that antitumor immune capacity is maintained among local dendritic cell subpopulations in the tumor environment with cancer progression. Similar dendritic cell subsets are present in malignant ascites from women with ovarian cancer, supporting the translational relevance of these results.
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Affiliation(s)
- Dallas B Flies
- Division of Gynecologic Oncology, University of New Mexico Comprehensive Cancer Center , Albuquerque, NM, USA
| | - Tomoe Higuchi
- Division of Gynecologic Oncology, University of New Mexico Comprehensive Cancer Center , Albuquerque, NM, USA
| | - Jaryse C Harris
- Division of Gynecologic Oncology, University of New Mexico Comprehensive Cancer Center , Albuquerque, NM, USA
| | - Vibha Jha
- Ovarian Cancer Research Center, The University of Pennsylvania , Philadelphia, PA, USA
| | - Phyllis A Gimotty
- Department of Biostatistics, The University of Pennsylvania , Philadelphia, PA, USA
| | - Sarah F Adams
- Division of Gynecologic Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA; Ovarian Cancer Research Center, The University of Pennsylvania, Philadelphia, PA, USA
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50
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Abstract
Founded on the growing insight into the complex cancer-immune system interactions, adjuvant immunotherapies are rapidly emerging and being adapted for the treatment of various human malignancies. Immune checkpoint inhibitors, for example, have already shown clinical success. Nevertheless, many approaches are not optimized, require frequent administration, are associated with systemic toxicities and only show modest efficacy as monotherapies. Nanotechnology can potentially enhance the efficacy of such immunotherapies by improving the delivery, retention and release of immunostimulatory agents and biologicals in targeted cell populations and tissues. This review presents the current status and emerging trends in such nanotechnology-based cancer immunotherapies including the role of nanoparticles as carriers of immunomodulators, nanoparticles-based cancer vaccines, and depots for sustained immunostimulation. Also highlighted are key translational challenges and opportunities in this rapidly growing field.
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Affiliation(s)
- Sourabh Shukla
- Department of Biomedical Engineering, Case
Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western
Reserve University, Cleveland, OH 44106, USA
| | - Nicole F Steinmetz
- Department of Biomedical Engineering, Case
Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western
Reserve University, Cleveland, OH 44106, USA
- Department of Radiology, Case Western Reserve
University, Cleveland, OH 44106, USA
- Department of Materials Science and
Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Macromolecular Science and
Engineering, Case Western Reserve University, Cleveland, OH 44106
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