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1
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Luri-Rey C, Teijeira Á, Wculek SK, de Andrea C, Herrero C, Lopez-Janeiro A, Rodríguez-Ruiz ME, Heras I, Aggelakopoulou M, Berraondo P, Sancho D, Melero I. Cross-priming in cancer immunology and immunotherapy. Nat Rev Cancer 2025; 25:249-273. [PMID: 39881005 DOI: 10.1038/s41568-024-00785-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 01/31/2025]
Abstract
Cytotoxic T cell immune responses against cancer crucially depend on the ability of a subtype of professional antigen-presenting cells termed conventional type 1 dendritic cells (cDC1s) to cross-present antigens. Cross-presentation comprises redirection of exogenous antigens taken from other cells to the major histocompatibility complex class I antigen-presenting machinery. In addition, once activated and having sensed viral moieties or T helper cell cooperation via CD40-CD40L interactions, cDC1s provide key co-stimulatory ligands and cytokines to mount and sustain CD8+ T cell immune responses. This regulated process of cognate T cell activation is termed cross-priming. In cancer mouse models, CD8+ T cell cross-priming by cDC1s is crucial for the efficacy of most, if not all, immunotherapy strategies. In patients with cancer, the presence and abundance of cDC1s in the tumour microenvironment is markedly associated with the level of T cell infiltration and responsiveness to immune checkpoint inhibitors. Therapeutic strategies to increase the numbers of cDC1s using FMS-like tyrosine kinase 3 ligand (FLT3L) and/or their activation status show evidence of efficacy in cancer mouse models and are currently being tested in initial clinical trials with promising results so far.
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Affiliation(s)
- Carlos Luri-Rey
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
| | - Álvaro Teijeira
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Stefanie K Wculek
- Innate Immune Biology Laboratory, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Carlos de Andrea
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Claudia Herrero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
| | | | | | - Ignacio Heras
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | | | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - David Sancho
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain.
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Departments of Immunology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
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2
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Yanik S, Venkatesh V, Gordy JT, Alameh MG, Meza J, Li Y, Glass E, Flores-Garcia Y, Tam Y, Chaiyawong N, Sarkar D, Weissman D, Markham R, Srinivasan P. iDC-targeting PfCSP mRNA vaccine confers superior protection against Plasmodium compared to conventional mRNA. NPJ Vaccines 2025; 10:34. [PMID: 39971939 PMCID: PMC11840135 DOI: 10.1038/s41541-025-01089-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025] Open
Abstract
Malaria resurgence in 2022 saw 249 million clinical cases and 608,000 deaths, mostly in children under five. The WHO-approved circumsporozoite protein (CSP)-targeting vaccines, RTS,S and R21, remain limited in availability. Strong humoral responses are crucial for sporozoite neutralization before hepatocyte infection, yet first-generation vaccines provide suboptimal protection, necessitating improved strategies. With the success of mRNA-LNP vaccines against COVID-19, there is interest in leveraging this approach to malaria. Here, we developed a novel chemokine fusion mRNA vaccine targeting immature dendritic cells (iDC) to enhance immunity against P. falciparum CSP (PfCSP). Mice immunized with MIP3α-CSP mRNA-LNP exhibited stronger CD4 + T cell responses and higher anti-NANP6 antibody titers than conventional CSP mRNA-LNP. Importantly, upon P. berghei PfCSP transgenic sporozoite challenge, MIP3α-CSP mRNA provided significantly greater protection from liver infection, strongly associated with multifunctional CD4 + T cells and anti-NANP6 titers. This study underscores iDC targeting as a promising strategy to enhance malaria vaccine efficacy.
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Affiliation(s)
- Sean Yanik
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA
| | - Varsha Venkatesh
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA
| | - James T Gordy
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | | | - Jacob Meza
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Yangchen Li
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Elizabeth Glass
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Yevel Flores-Garcia
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA
| | - Ying Tam
- Acuitas Therapeutics, Vancouver, BC, Canada
| | - Nattawat Chaiyawong
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA
| | - Deepti Sarkar
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA
| | - Drew Weissman
- Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA
| | - Richard Markham
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Prakash Srinivasan
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, USA.
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, USA.
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3
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Shin HS, Kim H, Kwon SG, Lee H, Lee JO, Kim YS. Tumor cells ectopically expressing the membrane-bound form of IL-7 develop an antitumor immune response efficiently in a colon carcinoma model. Mol Cells 2025; 48:100175. [PMID: 39743142 PMCID: PMC11873615 DOI: 10.1016/j.mocell.2024.100175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/20/2024] [Accepted: 12/25/2024] [Indexed: 01/04/2025] Open
Abstract
Various approaches employing cytokines and cytokine gene-modified tumor cells have been explored to induce antitumor responses, yet their widespread application has been limited due to efficacy concerns and adverse effects. In this study, interleukin-7 was engineered for expression both as a natural secretory form (sIL-7) and as a membrane-bound form fused with the B7.1 type I transmembrane protein (mbIL-7/B7) on CT26 colon cancer cells. Analysis of the resulting cell clones demonstrated that ectopically expressed sIL-7 and mbIL-7/B7 both retained similar capacities to induce the expansion and activation of CD8+ T cells and to enhance antitumor responses in vitro. While the sIL-7 or mbIL-7/B7 clones showed similar growth in culture, the mbIL-7/B7 clone exhibited lower tumorigenicity in mice compared with the sIL-7 clone or wild-type CT26 cells. Specifically, the mbIL-7/B7 clone failed to form tumors in approximately 60% of the mice injected with it. Moreover, 80% of mice that rejected the mbIL-7/B7 clone developed long-term systemic immunity against CT26 cells. Analysis of immune cells within the tumor masses revealed significant increases in CD4+ T cells, CD8+ T cells, and dendritic cells in tumors formed by the mbIL-7/B7 clone compared to those formed by the sIL-7 clone. These findings suggest that the membrane-bound form of IL-7 with B7.1 is more effective than the secretory form in establishing antitumor immunity within the tumor microenvironment. Our strategy of expressing the mbIL-7/B7 chimera holds promise as a novel approach for tumor therapy, particularly in cases requiring IL-7 supplementation.
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Affiliation(s)
- Hee-Su Shin
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Korea
| | - Hyejin Kim
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Korea
| | - Soon-Gyu Kwon
- Department of Life Sciences and Institute of Membrane Proteins, POSTECH, Pohang 37673, Korea
| | - Hayyoung Lee
- Department of Life Sciences and Postech Biotech Center, POSTECH, Pohang 37673, Korea
| | - Jie-Oh Lee
- Department of Life Sciences and Institute of Membrane Proteins, POSTECH, Pohang 37673, Korea.
| | - Young Sang Kim
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Korea.
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4
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Chi WY, Hu Y, Huang HC, Kuo HH, Lin SH, Kuo CTJ, Tao J, Fan D, Huang YM, Wu AA, Hung CF, Wu TC. Molecular targets and strategies in the development of nucleic acid cancer vaccines: from shared to personalized antigens. J Biomed Sci 2024; 31:94. [PMID: 39379923 PMCID: PMC11463125 DOI: 10.1186/s12929-024-01082-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/01/2024] [Indexed: 10/10/2024] Open
Abstract
Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.
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Affiliation(s)
- Wei-Yu Chi
- Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Medicine, New York, NY, USA
| | - Yingying Hu
- Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hsin-Che Huang
- Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hui-Hsuan Kuo
- Pharmacology PhD Program, Weill Cornell Medicine, New York, NY, USA
| | - Shu-Hong Lin
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston and MD Anderson Cancer Center, Houston, TX, USA
| | - Chun-Tien Jimmy Kuo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Julia Tao
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Darrell Fan
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Yi-Min Huang
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Annie A Wu
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Obstetrics and Gynecology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - T-C Wu
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA.
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Department of Obstetrics and Gynecology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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5
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Yanik S, Venkatesh V, Gordy JT, Gabriel-Alameh M, Meza J, Li Y, Glass E, Flores-Garcia Y, Tam Y, Chaiyawong N, Sarkar D, Weissman D, Markham R, Srinivasan P. Immature dendritic cell-targeting mRNA vaccine expressing PfCSP enhances protective immune responses against Plasmodium liver infection. RESEARCH SQUARE 2024:rs.3.rs-4656309. [PMID: 39041038 PMCID: PMC11261966 DOI: 10.21203/rs.3.rs-4656309/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Resurgence in malaria has been noted in 2022 with 249 million clinical cases resulting in 608,000 deaths, mostly in children under five. Two vaccines, RTS, S, and more recently R21, targeting the circumsporozoite protein (CSP) are recommended by the WHO but are not yet widely available. Strong humoral responses to neutralize sporozoites before they can infect the hepatocytes are important for vaccine-mediated protection. Suboptimal protection conferred by these first-generation vaccines highlight the need for approaches to improve vaccine-induced immune responses. With the recent success of mRNA-LNP vaccines against COVID-19, there is growing interest in leveraging this approach to enhance malaria vaccines. Here, we present the development of a novel chemokine fusion mRNA vaccine aimed at boosting immune responses to PfCSP by targeting the immunogen to immature dendritic cells (iDC). Vaccination of mice with mRNA encoding full-length CSP fused to macrophage inflammatory protein 3 alpha (MIP3α) encapsulated within lipid nanoparticles (LNP) elicited robust CD4+ T cell responses and enhanced antibody titers against NANP repeat epitopes compared to a conventional CSP mRNA-LNP vaccine. Importantly, the CSP-MIP3α fusion vaccine provided significantly greater protection against liver infection upon challenge with P. berghei PfCSP transgenic sporozoites. This enhanced protection was associated with multifunctional CD4+ T cells levels and anti-NANP repeat titers. This study highlights the potential to augment immune responses to PfCSP through iDC targeting and bolster protection against malaria liver infection.
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Affiliation(s)
- Sean Yanik
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA
| | - Varsha Venkatesh
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA
| | - James T Gordy
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
| | | | - Jacob Meza
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
| | - Yangchen Li
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
| | - Elizabeth Glass
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
| | - Yevel Flores-Garcia
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA
| | - Ying Tam
- Acuitas Therapeutics, Vancouver, BC, Canada
| | - Nattawat Chaiyawong
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA
| | - Deepti Sarkar
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA
| | - Drew Weissman
- Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA 19104
| | - Richard Markham
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
| | - Prakash Srinivasan
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD, 21205, USA
- The Johns Hopkins Malaria Research Institute, Baltimore, MD, 21205, USA
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6
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Katsikis PD, Ishii KJ, Schliehe C. Challenges in developing personalized neoantigen cancer vaccines. Nat Rev Immunol 2024; 24:213-227. [PMID: 37783860 PMCID: PMC12001822 DOI: 10.1038/s41577-023-00937-y] [Citation(s) in RCA: 69] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2023] [Indexed: 10/04/2023]
Abstract
The recent success of cancer immunotherapies has highlighted the benefit of harnessing the immune system for cancer treatment. Vaccines have a long history of promoting immunity to pathogens and, consequently, vaccines targeting cancer neoantigens have been championed as a tool to direct and amplify immune responses against tumours while sparing healthy tissue. In recent years, extensive preclinical research and more than one hundred clinical trials have tested different strategies of neoantigen discovery and vaccine formulations. However, despite the enthusiasm for neoantigen vaccines, proof of unequivocal efficacy has remained beyond reach for the majority of clinical trials. In this Review, we focus on the key obstacles pertaining to vaccine design and tumour environment that remain to be overcome in order to unleash the true potential of neoantigen vaccines in cancer therapy.
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Affiliation(s)
- Peter D Katsikis
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands.
| | - Ken J Ishii
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
- International Vaccine Design Center (vDesC), The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
| | - Christopher Schliehe
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
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7
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Moussion C, Delamarre L. Antigen cross-presentation by dendritic cells: A critical axis in cancer immunotherapy. Semin Immunol 2024; 71:101848. [PMID: 38035643 DOI: 10.1016/j.smim.2023.101848] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023]
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in shaping adaptive immunity. DCs have a unique ability to sample their environment, capture and process exogenous antigens into peptides that are then loaded onto major histocompatibility complex class I molecules for presentation to CD8+ T cells. This process, called cross-presentation, is essential for initiating and regulating CD8+ T cell responses against tumors and intracellular pathogens. In this review, we will discuss the role of DCs in cancer immunity, the molecular mechanisms underlying antigen cross-presentation by DCs, the immunosuppressive factors that limit the efficiency of this process in cancer, and approaches to overcome DC dysfunction and therapeutically promote antitumoral immunity.
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Affiliation(s)
| | - Lélia Delamarre
- Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
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8
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Cai L, Mao J, Wang H, Chen G, Xu X, Yuan Q, Chen W. Application of DNA-based hydrogels as drug delivery system for immunomodulatory therapy. J Drug Deliv Sci Technol 2023; 86:104677. [DOI: 10.1016/j.jddst.2023.104677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
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9
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Clappaert EJ, Kancheva D, Brughmans J, Debraekeleer A, Bardet PMR, Elkrim Y, Lacroix D, Živalj M, Hamouda AE, Van Ginderachter JA, Deschoemaeker S, Laoui D. Flt3L therapy increases the abundance of Treg-promoting CCR7 + cDCs in preclinical cancer models. Front Immunol 2023; 14:1166180. [PMID: 37622122 PMCID: PMC10445485 DOI: 10.3389/fimmu.2023.1166180] [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: 02/14/2023] [Accepted: 07/25/2023] [Indexed: 08/26/2023] Open
Abstract
Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy.
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Affiliation(s)
- Emile J. Clappaert
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Daliya Kancheva
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Jan Brughmans
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ayla Debraekeleer
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Pauline M. R. Bardet
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Yvon Elkrim
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Dagmar Lacroix
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Maida Živalj
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Ahmed E.I. Hamouda
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jo A. Van Ginderachter
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Sofie Deschoemaeker
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Damya Laoui
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
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10
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Goenka A, Khan F, Verma B, Sinha P, Dmello CC, Jogalekar MP, Gangadaran P, Ahn B. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun (Lond) 2023; 43:525-561. [PMID: 37005490 PMCID: PMC10174093 DOI: 10.1002/cac2.12416] [Citation(s) in RCA: 107] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/22/2023] [Accepted: 03/20/2023] [Indexed: 04/04/2023] Open
Abstract
Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF-β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD-1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C-C chemokine receptor 4 (CCR4)- C-C class chemokines 22 (CCL22)/ and 17 (CCL17), C-C chemokine receptor type 2 (CCR2)- chemokine (C-C motif) ligand 2 (CCL2), C-C chemokine receptor type 5 (CCR5)- chemokine (C-C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.
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Affiliation(s)
- Anshika Goenka
- The Ken & Ruth Davee Department of NeurologyThe Robert H. Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago, 60611ILUSA
| | - Fatima Khan
- Department of Neurological SurgeryFeinberg School of MedicineNorthwestern UniversityChicago, 60611ILUSA
| | - Bhupender Verma
- Department of OphthalmologySchepens Eye Research InstituteMassachusetts Eye and Ear InfirmaryHarvard Medical SchoolBoston, 02114MAUSA
| | - Priyanka Sinha
- Department of NeurologyMassGeneral Institute for Neurodegenerative DiseaseMassachusetts General Hospital, Harvard Medical SchoolCharlestown, 02129MAUSA
| | - Crismita C. Dmello
- Department of Neurological SurgeryFeinberg School of MedicineNorthwestern UniversityChicago, 60611ILUSA
| | - Manasi P. Jogalekar
- Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoSan Francisco, 94143CAUSA
| | - Prakash Gangadaran
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future TalentsDepartment of Biomedical Science, School of MedicineKyungpook National UniversityDaegu, 41944South Korea
- Department of Nuclear MedicineSchool of Medicine, Kyungpook National University, Kyungpook National University HospitalDaegu, 41944South Korea
| | - Byeong‐Cheol Ahn
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future TalentsDepartment of Biomedical Science, School of MedicineKyungpook National UniversityDaegu, 41944South Korea
- Department of Nuclear MedicineSchool of Medicine, Kyungpook National University, Kyungpook National University HospitalDaegu, 41944South Korea
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11
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Savage TM, Vincent RL, Rae SS, Huang LH, Ahn A, Pu K, Li F, de los Santos-Alexis K, Coker C, Danino T, Arpaia N. Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity. SCIENCE ADVANCES 2023; 9:eadc9436. [PMID: 36888717 PMCID: PMC9995032 DOI: 10.1126/sciadv.adc9436] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 02/07/2023] [Indexed: 05/28/2023]
Abstract
Tumors use multiple mechanisms to actively exclude immune cells involved in antitumor immunity. Strategies to overcome these exclusion signals remain limited due to an inability to target therapeutics specifically to the tumor. Synthetic biology enables engineering of cells and microbes for tumor-localized delivery of therapeutic candidates previously unavailable using conventional systemic administration techniques. Here, we engineer bacteria to intratumorally release chemokines to attract adaptive immune cells into the tumor environment. Bacteria expressing an activating mutant of the human chemokine CXCL16 (hCXCL16K42A) offer therapeutic benefit in multiple mouse tumor models, an effect mediated via recruitment of CD8+ T cells. Furthermore, we target the presentation of tumor-derived antigens by dendritic cells, using a second engineered bacterial strain expressing CCL20. This led to type 1 conventional dendritic cell recruitment and synergized with hCXCL16K42A-induced T cell recruitment to provide additional therapeutic benefit. In summary, we engineer bacteria to recruit and activate innate and adaptive antitumor immune responses, offering a new cancer immunotherapy strategy.
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Affiliation(s)
- Thomas M. Savage
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Rosa L. Vincent
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Sarah S. Rae
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Lei Haley Huang
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Alexander Ahn
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Kelly Pu
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Fangda Li
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | | | - Courtney Coker
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Tal Danino
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Data Science Institute, Columbia University, New York, NY, USA
| | - Nicholas Arpaia
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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12
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Jia SN, Han YB, Yang R, Yang ZC. Chemokines in colon cancer progression. Semin Cancer Biol 2022; 86:400-407. [PMID: 35183412 DOI: 10.1016/j.semcancer.2022.02.007] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/27/2023]
Abstract
Colon cancer is a major human cancer accounting for about a tenth of all cancer cases thus making it among the top three cancers in terms of incidence as well as mortality. Metastasis to distant organs, particularly to liver, is the primary reason for associated mortality. Chemokines, the chemo-attractants for various immune cells, have increasingly been reported to be involved in cancer initiation and progression, including in colon cancer. Here we discuss the available knowledge on the role of several chemokines, such as, CCL2, CCL3, CCL5, CXCL1, CXCL2, CXCL8 in colon cancer progression. CCL20 is one chemokine with emerging evidence for its role in influencing colon cancer tumor microenvironment through the documents effects on fibroblasts, macrophages and immune cells. We focus on CCL20 and its receptor CCR6 as promising factors that affect multiple levels of colon cancer progression. They interact with several cytokines and TLR receptors leading to increased aggressiveness, as supported by multitude of evidence from in vitro, in vivo studies as well as human patient samples. CCL20-CCR6 bring about their biological effects through regulation of several signaling pathways, including, ERK and NF-κB pathways, in addition to the epithelial-mesenchymal transition. Signaling involving CCL20-CCR6 has profound effect on colon cancer hepatic metastasis. Combined with elevated CCL20 levels in colon tumors and metastatic patients, the above information points to a need for further evaluation of chemokines as diagnostic and/or prognostic biomarkers.
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Affiliation(s)
- Sheng-Nan Jia
- Department of HepatoPancreatoBiliary Medicine, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Ying-Bo Han
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Rui Yang
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Ze-Cheng Yang
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000, China.
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13
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Kohli K, Pillarisetty VG, Kim TS. Key chemokines direct migration of immune cells in solid tumors. Cancer Gene Ther 2022; 29:10-21. [PMID: 33603130 PMCID: PMC8761573 DOI: 10.1038/s41417-021-00303-x] [Citation(s) in RCA: 284] [Impact Index Per Article: 94.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/18/2021] [Accepted: 01/28/2021] [Indexed: 01/31/2023]
Abstract
Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.
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Affiliation(s)
- Karan Kohli
- grid.34477.330000000122986657University of Washington, Department of Surgery, Seattle, WA USA
| | - Venu G. Pillarisetty
- grid.34477.330000000122986657University of Washington, Department of Surgery, Seattle, WA USA
| | - Teresa S. Kim
- grid.34477.330000000122986657University of Washington, Department of Surgery, Seattle, WA USA
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14
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Yan WL, Wu CC, Shen KY, Liu SJ. Activation of GM-CSF and TLR2 signaling synergistically enhances antigen-specific antitumor immunity and modulates the tumor microenvironment. J Immunother Cancer 2021; 9:jitc-2021-002758. [PMID: 34599024 PMCID: PMC8488721 DOI: 10.1136/jitc-2021-002758] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2021] [Indexed: 01/21/2023] Open
Abstract
Background The major challenge of antitumor immunotherapy is dealing with the immunosuppressive tumor microenvironment, which involves immature myeloid cell accumulation that results in T cell dysfunction. Myeloid cell activation is induced by Toll-like receptor agonists. Additionally, granulocyte/macrophage colony stimulating factor (GM-CSF) promotes myelopoiesis and recruits myeloid cells. Here, we combined the Toll-like receptor 2 (TLR2) agonist lipoprotein and GM-CSF to assess whether this bifunctional immunotherapy has synergistic effects on myeloid cells and could be further developed as a therapeutic intervention that enhances the antitumor response. Methods We investigated the synergistic effects of biadjuvanted tumor antigen on antigen-presenting cell (APC) activation in bone marrow-derived dendritic cells. Furthermore, therapeutic efficacy was monitored in different tumor models treated via intratumoral or subcutaneous administration routes. The immune effects of the bifunctional fusion protein on myeloid cells in the tumor mass and draining lymph nodes were analyzed by flow cytometry. The induction of cytotoxic T lymphocytes was evaluated via intracellular cytokine levels, perforin/granzyme B staining and an in vivo killing assay. Results The TLR2 agonist lipoprotein combined with GM-CSF synergistically induced DC maturation, which subsequently enhanced antitumor immunity. In addition, rlipoE7m-MoGM modulated tumor-infiltrating myeloid cell populations. Vaccination with rlipoE7m-MoGM therapy increased the number of CCR7+CD103+ cDC1s, whereas the number of suppressive tumor-associated macrophages was reduced in the tumor lesions. Consistent with this observation, proliferating antigen-specific CD8+ T cells are highly infiltrated within the tumor, and the expression of IFN-r and perforin was most pronounced within antigen-specific CD8+ T cells in mice administered rlipoE7m-MoGM therapy. This finding corresponded with observation that the combination of a TLR2 agonist and GM-CSF provides increased antitumor activity by inhibiting established tumor outgrowth and protecting against metastatic cancer compared with a TLR2 agonist alone. Importantly, tumor growth inhibition was not due to the direct effects of the TLR2 agonist or GM-CSF but was instead due to the induction of antigen-specific immunity. Conclusions The combination of a TLR2 agonist and GM-CSF has synergistic effects that inhibit tumor growth and modulate tumor-infiltrating APCs. This therapeutic approach could be applied to other tumor antigens to treat different cancers.
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Affiliation(s)
- Wan-Lun Yan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.,National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
| | - Chiao-Chieh Wu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
| | - Kuan-Yin Shen
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.,School of Dentistry, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
| | - Shih-Jen Liu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan .,National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.,Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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15
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Cueto FJ, Sancho D. The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy. Cancers (Basel) 2021; 13:1525. [PMID: 33810248 PMCID: PMC8037622 DOI: 10.3390/cancers13071525] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 12/19/2022] Open
Abstract
Dendritic cells (DCs) prime anti-tumor T cell responses in tumor-draining lymph nodes and can restimulate T effector responses in the tumor site. Thus, in addition to unleashing T cell effector activity, current immunotherapies should be directed to boost DC function. Herein, we review the potential function of Flt3L as a tool for cancer immunotherapy. Flt3L is a growth factor that acts in Flt3-expressing multipotent progenitors and common lymphoid progenitors. Despite the broad expression of Flt3 in the hematopoietic progenitors, the main effect of the Flt3/Flt3L axis, revealed by the characterization of mice deficient in these genes, is the generation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). However, Flt3 signaling through PI3K and mTOR may also affect the function of mature DCs. We recapitulate the use of Flt3L in preclinical studies either as a single agent or in combination with other cancer therapies. We also analyze the use of Flt3L in clinical trials. The strong correlation between type 1 cDC (cDC1) infiltration of human cancers with overall survival in many cancer types suggests the potential use of Flt3L to boost expansion of this DC subset. However, this may need the combination of Flt3L with other immunomodulatory agents to boost cancer immunotherapy.
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Affiliation(s)
- Francisco J. Cueto
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - David Sancho
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
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16
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Raaijmakers TK, van den Bijgaart RJE, den Brok MH, Wassink M, de Graaf A, Wagenaars JA, Nierkens S, Ansems M, Scheffer GJ, Adema GJ. Tumor ablation plus co-administration of CpG and saponin adjuvants affects IL-1 production and multifunctional T cell numbers in tumor draining lymph nodes. J Immunother Cancer 2021; 8:jitc-2020-000649. [PMID: 32461350 PMCID: PMC7254152 DOI: 10.1136/jitc-2020-000649] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2020] [Indexed: 12/25/2022] Open
Abstract
Background Tumor ablation techniques, like cryoablation, are successfully used in the clinic to treat tumors. The tumor debris remaining in situ after ablation is a major antigen depot, including neoantigens, which are presented by dendritic cells (DCs) in the draining lymph nodes to induce tumor-specific CD8+ T cells. We have previously shown that co-administration of adjuvants is essential to evoke strong in vivo antitumor immunity and the induction of long-term memory. However, which adjuvants most effectively combine with in situ tumor ablation remains unclear. Methods and results Here, we show that simultaneous administration of cytidyl guanosyl (CpG) with saponin-based adjuvants following cryoablation affects multifunctional T-cell numbers and interleukin (IL)-1 induced polymorphonuclear neutrophil recruitment in the tumor draining lymph nodes, relative to either adjuvant alone. The combination of CpG and saponin-based adjuvants induces potent DC maturation (mainly CpG-mediated), antigen cross-presentation (mainly saponin-based adjuvant mediated), while excretion of IL-1β by DCs in vitro depends on the presence of both adjuvants. Most strikingly, CpG/saponin-based adjuvant exposed DCs potentiate antigen-specific T-cell proliferation resulting in multipotent T cells with increased capacity to produce interferon (IFN)γ, IL-2 and tumor necrosis factor-α in vitro. Also in vivo the CpG/saponin-based adjuvant combination plus cryoablation increased the numbers of tumor-specific CD8+ T cells showing enhanced IFNγ production as compared with single adjuvant treatments. Conclusions Collectively, these data indicate that co-injection of CpG with saponin-based adjuvants after cryoablation induces an increased amount of tumor-specific multifunctional T cells. The combination of saponin-based adjuvants with toll-like receptor 9 adjuvant CpG in a cryoablative setting therefore represents a promising in situ vaccination strategy.
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Affiliation(s)
- Tonke K Raaijmakers
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Renske J E van den Bijgaart
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn H den Brok
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Melissa Wassink
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Annemarie de Graaf
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jori A Wagenaars
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Stefan Nierkens
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.,Center for Translational Immunology, Utrecht University, Utrecht, The Netherlands
| | - Marleen Ansems
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gert Jan Scheffer
- Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gosse J Adema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
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17
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Klarquist JS, Janssen EM. Melanoma-infiltrating dendritic cells: Limitations and opportunities of mouse models. Oncoimmunology 2021; 1:1584-1593. [PMID: 23264904 PMCID: PMC3525613 DOI: 10.4161/onci.22660] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The infiltration of melanoma lesions by dendritic cells (DCs) has been suggested to play a tumorigenic role due to the capacity of DCs to induce tumor tolerance and promote angiogenesis as well as metastasis. However, it has also been shown that tumor-infiltrating DCs (TIDCs) induce antitumor responses and hence may be targeted in cost-effective therapeutic approaches to obtain patient-specific DCs that present relevant tumor antigens, without the need for ex vivo DC expansion or tumor antigen identification. Unfortunately, little is known about the composition, nature and function of TIDCs found in human melanoma. The development of mouse melanoma models has greatly contributed to the molecular understanding of melanoma immunology in mice, but many questions on TIDCs remain unanswered. Here, we discuss current knowledge about melanoma TIDCs in various mouse models with regard to their translational potential and clinical relevance.
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Affiliation(s)
- Jared S Klarquist
- Division of Cellular and Molecular Immunology; Cincinnati Children's Hospital Research Foundation; University of Cincinnati College of Medicine; Cincinnati, OH USA
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18
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Marciscano AE, Anandasabapathy N. The role of dendritic cells in cancer and anti-tumor immunity. Semin Immunol 2021; 52:101481. [PMID: 34023170 PMCID: PMC8545750 DOI: 10.1016/j.smim.2021.101481] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 12/25/2022]
Abstract
Dendritic cells (DC) are key sentinels of the host immune response with an important role in linking innate and adaptive immunity and maintaining tolerance. There is increasing recognition that DC are critical determinants of initiating and sustaining effective T-cell-mediated anti-tumor immune responses. Recent progress in immuno-oncology has led to the evolving insight that the presence and function of DC within the tumor microenvironment (TME) may dictate efficacy of cancer immunotherapies as well as conventional cancer therapies, including immune checkpoint blockade, radiotherapy and chemotherapy. As such, improved understanding of dendritic cell immunobiology specifically focusing on their role in T-cell priming, migration into tissues and TME, and the coordinated in vivo responses of functionally specialized DC subsets will facilitate a better mechanistic understanding of how tumor-immune surveillance can be leveraged to improve patient outcomes and to develop novel DC-targeted therapeutic approaches.
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Affiliation(s)
- Ariel E Marciscano
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, United States.
| | - Niroshana Anandasabapathy
- Department of Dermatology, Meyer Cancer Center, Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, United States; Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, New York, NY, United States.
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19
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Prokopi A, Tripp CH, Tummers B, Hornsteiner F, Spoeck S, Crawford JC, Clements DR, Efremova M, Hutter K, Bellmann L, Cappellano G, Cadilha BL, Kobold S, Boon L, Ortner D, Trajanoski Z, Chen S, de Gruijl TD, Idoyaga J, Green DR, Stoitzner P. Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy. J Immunother Cancer 2021; 9:jitc-2020-000832. [PMID: 33408092 PMCID: PMC7789456 DOI: 10.1136/jitc-2020-000832] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Immunotherapy with checkpoint inhibitors has shown impressive results in patients with melanoma, but still many do not benefit from this line of treatment. A lack of tumor-infiltrating T cells is a common reason for therapy failure but also a loss of intratumoral dendritic cells (DCs) has been described. METHODS We used the transgenic tg(Grm1)EPv melanoma mouse strain that develops spontaneous, slow-growing tumors to perform immunological analysis during tumor progression. With flow cytometry, the frequencies of DCs and T cells at different tumor stages and the expression of the inhibitory molecules programmed cell death protein-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells were analyzed. This was complemented with RNA-sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR) analysis to investigate the immune status of the tumors. To boost DC numbers and function, we administered Fms-related tyrosine 3 ligand (Flt3L) plus an adjuvant mix of polyI:C and anti-CD40. To enhance T cell function, we tested several checkpoint blockade antibodies. Immunological alterations were characterized in tumor and tumor-draining lymph nodes (LNs) by flow cytometry, CyTOF, microarray and RT-qPCR to understand how immune cells can control tumor growth. The specific role of migratory skin DCs was investigated by coculture of sorted DC subsets with melanoma-specific CD8+ T cells. RESULTS Our study revealed that tumor progression is characterized by upregulation of checkpoint molecules and a gradual loss of the dermal conventional DC (cDC) 2 subset. Monotherapy with checkpoint blockade could not restore antitumor immunity, whereas boosting DC numbers and activation increased tumor immunogenicity. This was reflected by higher numbers of activated cDC1 and cDC2 as well as CD4+ and CD8+ T cells in treated tumors. At the same time, the DC boost approach reinforced migratory dermal DC subsets to prime gp100-specific CD8+ T cells in tumor-draining LNs that expressed PD-1/TIM-3 and produced interferon γ (IFNγ)/tumor necrosis factor α (TNFα). As a consequence, the combination of the DC boost with antibodies against PD-1 and TIM-3 released the brake from T cells, leading to improved function within the tumors and delayed tumor growth. CONCLUSIONS Our results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy.
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Affiliation(s)
- Anastasia Prokopi
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph H Tripp
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Bart Tummers
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Florian Hornsteiner
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Sarah Spoeck
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jeremy Chase Crawford
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Derek R Clements
- Department of Micobiology & Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Mirjana Efremova
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Katharina Hutter
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Lydia Bellmann
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Giuseppe Cappellano
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Bruno L Cadilha
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany.,Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany.,Member of the German Center for Lung Research (DZL), Munich, Germany.,German Center for Translational Cancer Research (DKTK), partner site Munich, Munich, Germany
| | | | - Daniela Ortner
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Zlatko Trajanoski
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Suzie Chen
- Ernest Mario School of Pharmacy and Rutgers Cancer Institute, Rutgers University, New Brunswick, New Jersey, USA
| | - Tanja D de Gruijl
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Juliana Idoyaga
- Department of Micobiology & Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Patrizia Stoitzner
- Department of Dermatology, Venereology & Allergology, Medical University of Innsbruck, Innsbruck, Austria
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20
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Burn OK, Prasit KK, Hermans IF. Modulating the Tumour Microenvironment by Intratumoural Injection of Pattern Recognition Receptor Agonists. Cancers (Basel) 2020; 12:E3824. [PMID: 33352882 PMCID: PMC7765936 DOI: 10.3390/cancers12123824] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/16/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Signalling through pattern recognition receptors (PRRs) leads to strong proinflammatory responses, enhancing the activity of antigen presenting cells and shaping adaptive immune responses against tumour associated antigens. Unfortunately, toxicities associated with systemic administration of these agonists have limited their clinical use to date. Direct injection of PRR agonists into the tumour can enhance immune responses by directly modulating the cells present in the tumour microenvironment. This can improve local antitumour activity, but importantly, also facilitates systemic responses that limit tumour growth at distant sites. As such, this form of therapy could be used clinically where metastatic tumour lesions are accessible, or as neoadjuvant therapy. In this review, we summarise current preclinical data on intratumoural administration of PRR agonists, including new strategies to optimise delivery and impact, and combination studies with current and promising new cancer therapies.
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Affiliation(s)
- Olivia K. Burn
- Malaghan Institute of Medical Research, P.O. Box 7060, Wellington 6042, New Zealand; (O.K.B.); (K.K.P.)
- Maurice Wilkins Centre, Private Bag 92019, Auckland 1042, New Zealand
| | - Kef K. Prasit
- Malaghan Institute of Medical Research, P.O. Box 7060, Wellington 6042, New Zealand; (O.K.B.); (K.K.P.)
- Maurice Wilkins Centre, Private Bag 92019, Auckland 1042, New Zealand
| | - Ian F. Hermans
- Malaghan Institute of Medical Research, P.O. Box 7060, Wellington 6042, New Zealand; (O.K.B.); (K.K.P.)
- Maurice Wilkins Centre, Private Bag 92019, Auckland 1042, New Zealand
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21
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Abdou P, Wang Z, Chen Q, Chan A, Zhou DR, Gunadhi V, Gu Z. Advances in engineering local drug delivery systems for cancer immunotherapy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1632. [PMID: 32255276 PMCID: PMC7725287 DOI: 10.1002/wnan.1632] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 12/13/2022]
Abstract
Cancer immunotherapy aims to leverage the immune system to suppress the growth of tumors and to inhibit metastasis. The recent promising clinical outcomes associated with cancer immunotherapy have prompted research and development efforts towards enhancing the efficacy of immune checkpoint blockade, cancer vaccines, cytokine therapy, and adoptive T cell therapy. Advancements in biomaterials, nanomedicine, and micro-/nano-technology have facilitated the development of enhanced local delivery systems for cancer immunotherapy, which can enhance treatment efficacy while minimizing toxicity. Furthermore, locally administered cancer therapies that combine immunotherapy with chemotherapy, radiotherapy, or phototherapy have the potential to achieve synergistic antitumor effects. Herein, the latest studies on local delivery systems for cancer immunotherapy are surveyed, with an emphasis on the therapeutic benefits associated with the design of biomaterials and nanomedicines. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Peter Abdou
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Zejun Wang
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Qian Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren’ai Road, Suzhou, 215123, Jiangsu, PR China
| | - Amanda Chan
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Daojia R. Zhou
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
| | - Vivienne Gunadhi
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
| | - Zhen Gu
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA
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22
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EGFR/Ras-induced CCL20 production modulates the tumour microenvironment. Br J Cancer 2020; 123:942-954. [PMID: 32601464 PMCID: PMC7493992 DOI: 10.1038/s41416-020-0943-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 04/07/2020] [Accepted: 05/28/2020] [Indexed: 12/14/2022] Open
Abstract
Background The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. Methods The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo. Results Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system. Conclusion We propose that the chemokine axis CCL20–CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
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23
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Castiello L, Aricò E, D'Agostino G, Santodonato L, Belardelli F. In situ Vaccination by Direct Dendritic Cell Inoculation: The Coming of Age of an Old Idea? Front Immunol 2019; 10:2303. [PMID: 31611878 PMCID: PMC6773832 DOI: 10.3389/fimmu.2019.02303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 09/11/2019] [Indexed: 12/18/2022] Open
Abstract
For more than 25 years, dendritic cell (DC) based vaccination has flashily held promises to represent a therapeutic approach for cancer treatment. While the vast majority of studies has focused on the use of antigen loaded DC, the intratumoral delivery of unloaded DC aiming at in situ vaccination has gained much less attention. Such approach grounds on the ability of inoculated DC to internalize and process antigens directly released by tumor (usually in combination with cell-death-inducing agents) to activate broad patient-specific antitumor T cell response. In this review, we highlight the recent studies in both solid and hematological tumors showing promising clinical results and discuss the main pitfalls and advantages of this approach for endogenous cancer vaccination. Lastly, we discuss how in situ vaccination by DC inoculation may fit with current immunotherapy approaches to expand and prolong patient response.
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Affiliation(s)
- Luciano Castiello
- FaBioCell, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - Eleonora Aricò
- FaBioCell, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | | | - Laura Santodonato
- FaBioCell, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - Filippo Belardelli
- Consiglio Nazionale Delle Ricerche, Institute of Translational Pharmacology, Rome, Italy
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24
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The role of bacterial toxins and spores in cancer therapy. Life Sci 2019; 235:116839. [PMID: 31499068 DOI: 10.1016/j.lfs.2019.116839] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 08/21/2019] [Accepted: 09/04/2019] [Indexed: 12/16/2022]
Abstract
Cancer is one of the leading causes of human death worldwide. Conventional anticancer therapies are ineffective in treating cancer patients due to various reasons. Thus, more effective and accessible alternative anticancer strategies have been evolved with time with high specificity towards tumor cells and with less or no adverse effects to normal cells. One such promising therapy is the use of bacterial toxins and spores to treat advanced solid tumors. Initially, Coley paved the way towards the bacterial anticancer therapy several decades ago and now it has emerged as a potential tool to eliminate tumor cells. Bacterial spores of obligate anaerobes exclusively germinate in the hypoxic/necrotic areas and not in the well-oxygenated areas of the body. This unique phenomenon has been exploited in using bacterial spores as a remedy for cancer. Bacterial toxins also play a significant role in either directly killing tumor cells or altering the cellular processes of the tumor cells which ultimately leads to the inhibition and regression of the solid tumor. With the advancement of molecular techniques, a number of genetically-modified non-pathogenic bacteria have been developed to use in bacterial anticancer strategies. Although promising results have shown so far, further investigations are required to ensure the efficacy and the safety of the bacterial spores and toxins in treating cancer.
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25
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Sedighi M, Zahedi Bialvaei A, Hamblin MR, Ohadi E, Asadi A, Halajzadeh M, Lohrasbi V, Mohammadzadeh N, Amiriani T, Krutova M, Amini A, Kouhsari E. Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer Med 2019; 8:3167-3181. [PMID: 30950210 PMCID: PMC6558487 DOI: 10.1002/cam4.2148] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 03/17/2019] [Accepted: 03/20/2019] [Indexed: 12/26/2022] Open
Abstract
Successful treatment of cancer remains a challenge, due to the unique pathophysiology of solid tumors, and the predictable emergence of resistance. Traditional methods for cancer therapy including radiotherapy, chemotherapy, and immunotherapy all have their own limitations. A novel approach is bacteriotherapy, either used alone, or in combination with conventional methods, has shown a positive effect on regression of tumors and inhibition of metastasis. Bacteria-assisted tumor-targeted therapy used as therapeutic/gene/drug delivery vehicles has great promise in the treatment of tumors. The use of bacteria only, or in combination with conventional methods was found to be effective in some experimental models of cancer (tumor regression and increased survival rate). In this article, we reviewed the major advantages, challenges, and prospective directions for combinations of bacteria with conventional methods for tumor therapy.
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Affiliation(s)
- Mansour Sedighi
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Abed Zahedi Bialvaei
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Michael R. Hamblin
- Wellman Center for PhotomedicineMassachusetts General HospitalBostonMassachusetts
- Department of DermatologyHarvard Medical SchoolBostonMassachusetts
- Harvard‐MIT Division of Health Sciences and TechnologyCambridgeMassachusetts
| | - Elnaz Ohadi
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Arezoo Asadi
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Masoumeh Halajzadeh
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Vahid Lohrasbi
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Nima Mohammadzadeh
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
| | - Taghi Amiriani
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
| | - Marcela Krutova
- 2nd Faculty of Medicine, Department of Medical MicrobiologyCharles University and Motol University HospitalPragueCzech Republic
| | - Abolfazl Amini
- Laboratory Sciences Research CenterGolestan University of Medical SciencesGorganIran
| | - Ebrahim Kouhsari
- Department of Microbiology, School of MedicineIran University of Medical SciencesTehranIran
- Laboratory Sciences Research CenterGolestan University of Medical SciencesGorganIran
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26
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Samaniego R, Gutiérrez-González A, Gutiérrez-Seijo A, Sánchez-Gregorio S, García-Giménez J, Mercader E, Márquez-Rodas I, Avilés JA, Relloso M, Sánchez-Mateos P. CCL20 Expression by Tumor-Associated Macrophages Predicts Progression of Human Primary Cutaneous Melanoma. Cancer Immunol Res 2018; 6:267-275. [PMID: 29362221 DOI: 10.1158/2326-6066.cir-17-0198] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 10/03/2017] [Accepted: 01/09/2018] [Indexed: 11/16/2022]
Abstract
The chemokine axis CCR6/CCL20 is involved in cancer progression in a variety of tumors. Here, we show that CCR6 is expressed by melanoma cells. The CCR6 ligand, CCL20, induces migration and proliferation in vitro, and enhances tumor growth and metastasis in vivo Confocal analysis of melanoma tissues showed that CCR6 is expressed by tumor cells, whereas CCL20 is preferentially expressed by nontumoral cells in the stroma of certain tumors. Stromal CCL20, but not tumoral CCR6, predicted poor survival in a cohort of 40 primary melanoma patients. Tumor-associated macrophages (TAM), independently of their M1/M2 polarization profile, were identified as the main source of CCL20 in primary melanomas that developed metastasis. In addition to CCL20, TAMs expressed TNF and VEGF-A protumoral cytokines, suggesting that melanoma progression is supported by macrophages with a differential activation state. Our data highlight the synergistic interaction between melanoma tumor cells and prometastatic macrophages through a CCR6/CCL20 paracrine loop. Stromal levels of CCL20 in primary melanomas may be a clinically useful marker for assessing patient risk, making treatment decisions, and planning or analyzing clinical trials. Cancer Immunol Res; 6(3); 267-75. ©2018 AACR.
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Affiliation(s)
- Rafael Samaniego
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
| | | | - Alba Gutiérrez-Seijo
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Sandra Sánchez-Gregorio
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Jorge García-Giménez
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Enrique Mercader
- Servicio de Cirugía General, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - Iván Márquez-Rodas
- Servicio de Oncología, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - José Antonio Avilés
- Servicio de Dermatología, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - Miguel Relloso
- Grupo de Inmuno-fisiología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Paloma Sánchez-Mateos
- Laboratorio de Inmuno-oncología, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
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27
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Verma V, Kim Y, Lee MC, Lee JT, Cho S, Park IK, Min JJ, Lee JJ, Lee SE, Rhee JH. Activated dendritic cells delivered in tissue compatible biomatrices induce in-situ anti-tumor CTL responses leading to tumor regression. Oncotarget 2018; 7:39894-39906. [PMID: 27223090 PMCID: PMC5129979 DOI: 10.18632/oncotarget.9529] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 04/25/2016] [Indexed: 12/26/2022] Open
Abstract
Dendritic cell (DC) based anti-cancer immunotherapy is well tolerated in patients with advanced cancers. However, the clinical responses seen after adoptive DC therapy have been suboptimal. Several factors including scarce DC numbers in tumors and immunosuppressive tumor microenvironments contribute to the inefficacy of DCs as cellular vaccines. Hence DC based vaccines can benefit from novel methods of cell delivery that would prevent the direct exposure of immune cells to suppressive tumor microenvironments. Here we evaluated the ability of DCs harbored in biocompatible scaffolds (referred to as biomatrix entrapped DCs; beDCs) in activating specific anti-tumor immune responses against primary and post-surgery secondary tumors. Using a preclinical cervical cancer and a melanoma model in mice, we show that single treatment of primary and post-surgery secondary tumors using beDCs resulted in significant tumor growth retardation while multiple inoculations were required to achieve a significant anti-tumor effect when DCs were given in free form. Additionally, we found that, compared to the tumor specific E6/E7 peptide vaccine, total tumor lysate induced higher expression of CD80 and CD40 on DCs that induced increased levels of IFNγ production upon interaction with host lymphocytes. Remarkably, a strong immunocyte infiltration into the host-implanted DC-scaffold was observed. Importantly, the host-implanted beDCs induced the anti-tumor immune responses in the absence of any stromal cell support, and the biomatrix structure was eventually absorbed into the surrounding host tissue. Collectively, these data indicate that the scaffold-based DC delivery may provide an efficient and safe way of delivering cell-based vaccines for treatment of primary and post-surgery secondary tumors.
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Affiliation(s)
- Vivek Verma
- Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.,Department of Microbiology, Chonnam National University Medical School, Gwangju, South Korea.,Present address: GRU Cancer Center, GRU, Augusta, GA, USA
| | - Young Kim
- Department of Pathology, Chonnam National University Medical School, Gwangju, South Korea
| | - Min-Cheol Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, South Korea
| | - Jae-Tae Lee
- Department of Nuclear Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
| | - Sunghoon Cho
- School of Mechanical Systems Engineering, Chonnam National University, Gwangju, South Korea
| | - In-Kyu Park
- Department of Biomedical Science, Chonnam National University Medical School, Gwangju, South Korea
| | - Jung Joon Min
- Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, South Korea
| | - Je Jung Lee
- Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.,Research Center for Cancer Immunotherapy, Hwasun Hospital, Chonnam National University, Hwasun, South Korea
| | - Shee Eun Lee
- Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.,Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, South Korea
| | - Joon Haeng Rhee
- Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.,Department of Microbiology, Chonnam National University Medical School, Gwangju, South Korea
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28
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Nie Y, He J, Shirota H, Trivett AL, Yang D, Klinman DM, Oppenheim JJ, Chen X. Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer. Sci Signal 2018; 11:11/511/eaan0790. [PMID: 29295954 DOI: 10.1126/scisignal.aan0790] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Through the tumor necrosis factor (TNF) receptor type II (TNFR2), TNF preferentially activates, expands, and promotes the phenotypic stability of CD4+Foxp3+ regulatory T (Treg) cells. Those Treg cells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of Treg cells and consequently enhance the efficacy of cancer immunotherapy. We found that, relative to a suboptimal dose of the immunostimulatory Toll-like receptor 9 ligand CpG oligodeoxynucleotide (ODN), the combination of the suboptimal dose of CpG ODN with the TNFR2-blocking antibody M861 more markedly inhibited the growth of subcutaneously grafted mouse CT26 colon tumor cells. This resulted in markedly fewer TNFR2+ Treg cells and more interferon-γ-positive (IFN-γ+) CD8+ cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort. Tumor-free mice were resistant to rechallenge by the same but not unrelated (4T1 breast cancer) cells. Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer. Thus, the combination of a TNFR2 inhibitor and an immunotherapeutic stimulant may represent a more effective treatment strategy for various cancers.
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Affiliation(s)
- Yingjie Nie
- Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.,Department of Research, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Jiang He
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China
| | - Hidekazu Shirota
- Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Anna L Trivett
- Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - De Yang
- Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Dennis M Klinman
- Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Joost J Oppenheim
- Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China. .,Cancer Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
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29
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Marron TU, Hammerich L, Brody J. Local Immunotherapies of Cancer. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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30
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Ye JF, Qi WX, Liu MY, Li Y. The combination of NK and CD8+ T cells with CCL20/IL15-armed oncolytic adenoviruses enhances the growth suppression of TERT-positive tumor cells. Cell Immunol 2017; 318:35-41. [DOI: 10.1016/j.cellimm.2017.06.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/28/2017] [Accepted: 06/05/2017] [Indexed: 01/17/2023]
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31
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Enhanced efficacy of DNA vaccination against botulinum neurotoxin serotype A by co-administration of plasmids encoding DC-stimulating Flt3L and MIP-3α cytokines. Biologicals 2016; 44:441-7. [DOI: 10.1016/j.biologicals.2016.04.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 04/19/2016] [Accepted: 04/21/2016] [Indexed: 01/31/2023] Open
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32
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Saadeh D, Kurban M, Abbas O. Plasmacytoid dendritic cell role in cutaneous malignancies. J Dermatol Sci 2016; 83:3-9. [PMID: 27236509 DOI: 10.1016/j.jdermsci.2016.05.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/06/2016] [Accepted: 05/12/2016] [Indexed: 02/08/2023]
Abstract
Plasmacytoid dendritic cells (pDCs) correspond to a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, HLA-DR, blood-derived dendritic cell antigen-2 (BDCA-2), and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. Through their production of type I interferons (IFNs) and other pro-inflammatory cytokines, pDCs provide anti-viral resistance and link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer (NK) cells. While lacking from normal skin, pDCs are usually recruited to the skin in several cutaneous pathologies where they appear to be involved in the pathogenesis of several infectious, inflammatory/autoimmune, and neoplastic entities. Among the latter group, pDCs have the potential to induce anti-tumour immunity; however, the complex interaction of pDCs with tumor cells and their micro-environment appears to contribute to immunologic tolerance. In this review, we aim at highlighting the role played by pDCs in cutaneous malignancies with special emphasis on the underlying mechanisms.
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Affiliation(s)
- Dana Saadeh
- Dermatology Department, American University of Beirut Medical Center, Lebanon
| | - Mazen Kurban
- Dermatology Department, American University of Beirut Medical Center, Lebanon
| | - Ossama Abbas
- Dermatology Department, American University of Beirut Medical Center, Lebanon.
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33
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Hammerich L, Bhardwaj N, Kohrt HE, Brody JD. In situ vaccination for the treatment of cancer. Immunotherapy 2016; 8:315-30. [DOI: 10.2217/imt.15.120] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Vaccination has had a tremendous impact on human health by harnessing the immune system to prevent and eradicate infectious diseases and this same approach might be used in cancer therapy. Cancer vaccine development has been slowed hindered by the paucity of universal tumor-associated antigens and the difficulty in isolating and preparing individualized vaccines ex vivo. Another approach has been to initiate or stimulate an immune response in situ (at the tumor site) and thus exploit the potentially numerous tumor-associated antigens there. Here, we review the many approaches that have attempted to accomplish effective in situ vaccination, using intratumoral administration of immunomodulators to increase the numbers or activation state of either antigen present cells or T cells within the tumor.
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Affiliation(s)
- Linda Hammerich
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Nina Bhardwaj
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Holbrook E Kohrt
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Joshua D Brody
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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34
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Van Lint S, Renmans D, Broos K, Goethals L, Maenhout S, Benteyn D, Goyvaerts C, Du Four S, Van der Jeught K, Bialkowski L, Flamand V, Heirman C, Thielemans K, Breckpot K. Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells. Cancer Immunol Res 2015; 4:146-56. [DOI: 10.1158/2326-6066.cir-15-0163] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 10/23/2015] [Indexed: 01/02/2023]
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Hammerich L, Binder A, Brody JD. In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf. Mol Oncol 2015; 9:1966-81. [PMID: 26632446 PMCID: PMC5528727 DOI: 10.1016/j.molonc.2015.10.016] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 10/20/2015] [Accepted: 10/20/2015] [Indexed: 01/15/2023] Open
Abstract
As cancer immunotherapy continues to benefit from novel approaches which cut immune 'brake pedals' (e.g. anti-PD1 and anti-CTLA4 antibodies) and push immune cell gas pedals (e.g. IL2, and IFNα) there will be increasing need to develop immune 'steering wheels' such as vaccines to guide the immune system specifically toward tumor associated antigens. Two primary hurdles in cancer vaccines have been: identification of universal antigens to be used in 'off-the-shelf' vaccines for common cancers, and 2) logistical hurdles of ex vivo production of individualized whole tumor cell vaccines. Here we summarize approaches using 'in situ vaccination' in which intratumoral administration of off-the-shelf immunomodulators have been developed to specifically induce (or amplify) T cell responses to each patient's individual tumor. Clinical studies have confirmed the induction of systemic immune and clinical responses to such approaches and preclinical models have suggested ways to further potentiate the translation of in situ vaccine trials for our patients.
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Affiliation(s)
- Linda Hammerich
- Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, United States
| | - Adam Binder
- Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, United States
| | - Joshua D Brody
- Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, United States.
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Breitbach CJ, Parato K, Burke J, Hwang TH, Bell JC, Kirn DH. Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic. Curr Opin Virol 2015; 13:49-54. [DOI: 10.1016/j.coviro.2015.03.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/16/2015] [Accepted: 03/19/2015] [Indexed: 01/21/2023]
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Rossi AH, Farias A, Fernández JE, Bonomi HR, Goldbaum FA, Berguer PM. Brucella spp. Lumazine Synthase Induces a TLR4-Mediated Protective Response against B16 Melanoma in Mice. PLoS One 2015; 10:e0126827. [PMID: 25973756 PMCID: PMC4431812 DOI: 10.1371/journal.pone.0126827] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 04/07/2015] [Indexed: 02/03/2023] Open
Abstract
Brucella Lumazine Synthase (BLS) is a highly immunogenic decameric protein which can accept the fusion of foreign proteins at its ten N-termini. These chimeras are very efficient to elicit systemic and oral immunity without adjuvants. BLS signaling via Toll-Like Receptor 4 (TLR4) regulates innate and adaptive immune responses, inducing dendritic cell maturation and CD8+ T-cell cytotoxicity. In this work we study the effect induced by BLS in TLR4-expressing B16 melanoma. In order to evaluate the effectiveness of BLS as a preventive vaccine, C57BL/6J mice were immunized with BLS or BLS-OVA, and 35 days later were subcutaneously inoculated with B16-OVA melanoma. BLS or BLS-OVA induced a significant inhibition of tumor growth, and 50% of mice immunized with the highest dose of BLS did not develop visible tumors. This effect was not observed in TLR4-deficient mice. For treatment experiments, mice were injected with BLS or BLS-OVA 2 days after the inoculation of B16 cells. Both treatments induced significant and equal tumor growth delay and increased survival. Moreover, BLS and BLS-OVA stimulation were also effective in TLR4-deficient mice. In order to study whether BLS has a direct effect on tumor cells, B16 cells were preincubated with BLS, and after 48h, cells were inoculated. Tumors induced by BLS-stimulated cells had inhibited growth and survival was increased. In the BLS group, 40% of mice did not develop tumors. This effect was abolished by the addition of TLR4/MD2 blocking antibody to cells before BLS stimulation. Our work demonstrates that BLS immunization induces a preventive antitumor response that depends on mice TLR4. We also show that BLS generates a therapeutic effect in mice inoculated with B16 cells. Our results show that BLS acts directly in cultured tumor cells via TLR4, highly suggesting that BLS elicits its therapeutic effects acting on the TLR4 from B16 melanoma cells.
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Affiliation(s)
- Andrés H. Rossi
- Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Ana Farias
- Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Javier E. Fernández
- Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Hernán R. Bonomi
- Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Fernando A. Goldbaum
- Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Paula M. Berguer
- Fundación Instituto Leloir, IIBBA, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- * E-mail:
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Gardner JK, Mamotte CDS, Patel P, Yeoh TL, Jackaman C, Nelson DJ. Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function. PLoS One 2015; 10:e0123563. [PMID: 25886502 PMCID: PMC4401725 DOI: 10.1371/journal.pone.0123563] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 03/04/2015] [Indexed: 12/26/2022] Open
Abstract
Dendritic cells (DCs) play an important role in the generation of anti-cancer immune responses, however there is evidence that DCs in cancer patients are dysfunctional. Lipid accumulation driven by tumor-derived factors has recently been shown to contribute to DC dysfunction in several human cancers, but has not yet been examined in mesothelioma. This study investigated if mesothelioma tumor cells and/or their secreted factors promote increases in DC lipid content and modulate DC function. Human monocyte-derived DCs (MoDCs) were exposed to human mesothelioma tumor cells and tumor-derived factors in the presence or absence of lipoproteins. The data showed that immature MoDCs exposed to mesothelioma cells or factors contained increased lipid levels relative to control DCs. Lipid accumulation was associated with reduced antigen processing ability (measured using a DQ OVA assay), upregulation of the co-stimulatory molecule, CD86, and production of the tolerogenic cytokine, IL-10. Increases in DC lipid content were further enhanced by co-exposure to mesothelioma-derived factors and triglyceride-rich lipoproteins, but not low-density lipoproteins. In vivo studies using a murine mesothelioma model showed that the lipid content of tumor-infiltrating CD4+ CD8α- DCs, CD4- CD8α- DCs DCs and plasmacytoid DCs increased with tumor progression. Moreover, increasing tumor burden was associated with reduced proliferation of tumor-antigen-specific CD8+ T cells in tumor-draining lymph nodes. This study shows that mesothelioma promotes DC lipid acquisition, which is associated with altered activation status and reduced capacity to process and present antigens, which may impair the ability of DCs to generate effective anti mesothelioma T cell responses.
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Affiliation(s)
- Joanne K. Gardner
- Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia
| | - Cyril D. S. Mamotte
- CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia
| | - Priya Patel
- Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia
| | - Teong Ling Yeoh
- Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia
| | - Connie Jackaman
- Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia
| | - Delia J. Nelson
- Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia
- CHIRI Biosciences Research Precinct, Curtin University, Perth, Western Australia, Australia
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Huang FY, Huang FR, Chen B, Liu Q, Wang H, Zhou SL, Zhao HG, Huang YH, Lin YY, Tan GH. Microencapsulation of tumor lysates and live cell engineering with MIP-3α as an effective vaccine. Biomaterials 2015; 53:554-565. [PMID: 25890751 DOI: 10.1016/j.biomaterials.2015.02.123] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/25/2015] [Accepted: 02/27/2015] [Indexed: 10/23/2022]
Abstract
The combination of several potential strategies so as to develop new tumor vaccines is an attractive field of translational medicine. Pulsing tumor lysates with dendritic cells (DCs), in-vivo attraction of DCs by macrophage inflammatory protein 3α (MIP-3α), and reversion of the tumor suppressive microenvironment have been tested as strategies to develop tumor vaccines. In this study, we generated an alginate microsphere (named PaLtTcAdMIP3α) that encapsulated tumor lysates, live tumor cells engineering with a recombinant MIP-3α adenovirus and BCG. We used PaLtTcAdMIP3α as a model vaccine to test its antitumor activities. Our results showed that PaLtTcAdMIP3α expressed and excreted MIP-3α, which effectively attracted DCs ex vivo and in vivo. Injection of PaLtTcAdMIP3α into tumor-bearing mice effectively induced both therapeutic and prophylactic antitumor immunities in CT26, Meth A, B16-F10 and H22 models, but without any ensuing increase in adverse effects. Both tumor-specific cellular and humoral immune responses, especially the CD8(+) T cell-dependent cytotoxic T immunity, were found in the mice injected with PaLtTcAdMIP3α. The anti-tumor activity was abrogated completely by depletion of CD8(+) and partially by CD4(+) T lymphocytes. In addition, the number of IFN-γ-producing CD8(+) T cells in spleen and tumor tissues was significantly increased; but the number of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) in tumor tissues was decreased. These data strongly suggest that a combination of multi-current-using strategies such as the novel approach of using our PaLtTcAdMIP3α microspheres could be an effective tumor model vaccine.
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Affiliation(s)
- Feng-ying Huang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Feng-ru Huang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Bin Chen
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Quan Liu
- Oncology Institute, Fourth Affiliated Hospital of Soochow University, Wuxi 214062, China
| | - Hua Wang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Song-lin Zhou
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Huan-ge Zhao
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Yong-hao Huang
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Ying-ying Lin
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China
| | - Guang-hong Tan
- Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, China.
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40
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Lu Y, Yi Q. Utilizing T H9 cells as a novel therapeutic strategy for malignancies. Oncoimmunology 2014; 2:e23084. [PMID: 23802062 PMCID: PMC3661147 DOI: 10.4161/onci.23084] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 12/01/2012] [Indexed: 11/19/2022] Open
Abstract
TH9 cells join the ever-growing list of CD4+ T helper subsets and primarily mediate anti-parasite immune responses. We have recently demonstrated that tumor-specific TH9 cells induce a CCL20-CCR6-dependent regulation of DCs while stimulating CD8+ T cell-mediated antitumor immunity. These findings offer a novel immunotherapeutic strategy against cancer.
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Affiliation(s)
- Yong Lu
- Department of Lymphoma/Myeloma; Division of Cancer Medicine; Center for Cancer Immunology Research; The University of Texas MD Anderson Cancer Center; Houston, TX USA
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41
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Adenovirus-mediated CCL20/IL-15 gene transfer enhances antitumor immunity in mice. Immunobiology 2014; 219:475-81. [DOI: 10.1016/j.imbio.2014.02.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 12/29/2013] [Accepted: 02/20/2014] [Indexed: 12/11/2022]
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42
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Aspord C, Tramcourt L, Leloup C, Molens JP, Leccia MT, Charles J, Plumas J. Imiquimod inhibits melanoma development by promoting pDC cytotoxic functions and impeding tumor vascularization. J Invest Dermatol 2014; 134:2551-2561. [PMID: 24751730 DOI: 10.1038/jid.2014.194] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 03/06/2014] [Accepted: 04/08/2014] [Indexed: 11/09/2022]
Abstract
Imiquimod (IMQ) is a synthetic Toll-like receptor (TLR7/8) ligand that can trigger antiviral and antitumor activities. Despite evidence of potent therapeutic effects, the clinical use of IMQ in melanoma is impeded by incomplete understanding of its mechanisms of action. Mice and humans differ in many aspects of immunity, including TLR7 expression patterns, thus impeding the use of mouse models in translating discoveries into clinical applications. In this article, we investigated the mechanisms behind IMQ effects in vivo in a human context of melanoma and immunity using an innovative melanoma-bearing humanized mouse model. In this model, IMQ strongly inhibited melanoma tumor development through prompt mobilization of plasmacytoid dendritic cells and by triggering their cytotoxic functions, and through upregulation of expression of type 1 IFN response genes. IMQ also drastically impeded tumor vascularization by inducing the downregulation of angiogenic factors vascular endothelial growth factor, angiogenin, IL-8, and fibroblast growth factor. Our results revealed the short- and long-term multifactorial effects of IMQ converging toward inhibition of melanoma development. By providing a better understanding of the mechanisms of action of IMQ in melanoma, our study opens the way for its further clinical use in the treatment of metastatic melanoma.
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Affiliation(s)
- Caroline Aspord
- R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France.
| | - Laetitia Tramcourt
- R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France
| | - Claire Leloup
- R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France
| | - Jean-Paul Molens
- R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France
| | - Marie-Therese Leccia
- University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France; Department of Dermatology, Grenoble University Hospital, Grenoble, France
| | - Julie Charles
- University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France; Department of Dermatology, Grenoble University Hospital, Grenoble, France
| | - Joel Plumas
- R&D Laboratory, Etablissement Français du Sang Rhône-Alpes, La Tronche, France; University Joseph Fourier, Grenoble, France; Immunobiology & Immunotherapy of Cancers, U823, INSERM, La Tronche, France
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Zhao DX, Li ZJ, Zhang Y, Zhang XN, Zhao KC, Li YG, Zhang MM, Yu XW, Liu MY, Li Y. Enhanced antitumor immunity is elicited by adenovirus-mediated gene transfer of CCL21 and IL-15 in murine colon carcinomas. Cell Immunol 2014; 289:155-61. [PMID: 24838092 DOI: 10.1016/j.cellimm.2014.03.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 03/21/2014] [Accepted: 03/22/2014] [Indexed: 12/19/2022]
Abstract
The chemokine CCL21 is a potent chemoattractant for T cells and dendritic cells. IL-15 elicits powerful antitumor immune responses through the stimulation of natural killer cells. We constructed a CCL21/IL-15-expressing adenovirus (Ad-CCL21-IL-15) and evaluated its antitumor effects in vitro and in vivo. We found that the intratumoral injection of Ad-CCL21-IL-15 into murine colon carcinomas significantly inhibited tumor growth. Splenocytes from mice treated with Ad-CCL21-IL-15 developed tumor-specific cytotoxic T cells and were protected from subsequent challenges with tumor cells. This study indicates that providing cancer therapy by combining CCL21 and IL-15 can induce antitumor immune responses and is an effective strategy for cancer immunotherapy.
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Affiliation(s)
- Dong-xu Zhao
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, China-Japan Union Hospital, Jilin University, Changchun 130062, PR China
| | - Zhi-jie Li
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, PR China
| | - Yang Zhang
- First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Xiao-na Zhang
- First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Kun-chi Zhao
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, China-Japan Union Hospital, Jilin University, Changchun 130062, PR China
| | - Ya-gang Li
- Fourth Hospital of Jilin University, Changchun 130062, PR China
| | - Meng-meng Zhang
- Fourth Hospital of Jilin University, Changchun 130062, PR China
| | - Xiao-wei Yu
- First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Ming-yuan Liu
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, China-Japan Union Hospital, Jilin University, Changchun 130062, PR China; Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, PR China
| | - Yang Li
- Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, China-Japan Union Hospital, Jilin University, Changchun 130062, PR China.
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44
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Chaudhary B, Khaled YS, Ammori BJ, Elkord E. Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother 2014; 63:81-99. [PMID: 24263240 PMCID: PMC11028473 DOI: 10.1007/s00262-013-1500-0] [Citation(s) in RCA: 170] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 11/10/2013] [Indexed: 12/15/2022]
Abstract
Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.
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Affiliation(s)
- Belal Chaudhary
- Biomedical Research Centre, School of Environment and Life Sciences, University of Salford, The Crescent, Peel Building G25, Manchester, M5 4WT UK
| | - Yazan S. Khaled
- Biomedical Research Centre, School of Environment and Life Sciences, University of Salford, The Crescent, Peel Building G25, Manchester, M5 4WT UK
- Institutes of Cancer, Inflammation & Repair, University of Manchester, Manchester, UK
| | - Basil J. Ammori
- Biomedical Research Centre, School of Environment and Life Sciences, University of Salford, The Crescent, Peel Building G25, Manchester, M5 4WT UK
- Institutes of Cancer, Inflammation & Repair, University of Manchester, Manchester, UK
| | - Eyad Elkord
- Biomedical Research Centre, School of Environment and Life Sciences, University of Salford, The Crescent, Peel Building G25, Manchester, M5 4WT UK
- Institutes of Cancer, Inflammation & Repair, University of Manchester, Manchester, UK
- College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
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45
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Nitcheu Tefit J, Serra V. Outlining novel cellular adjuvant products for therapeutic vaccines against cancer. Expert Rev Vaccines 2014; 10:1207-20. [DOI: 10.1586/erv.11.84] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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46
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Li D, Wang W, Shi HS, Fu YJ, Chen X, Chen XC, Liu YT, Kan B, Wang YS. Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects. Hum Gene Ther 2013; 25:63-72. [PMID: 24134464 DOI: 10.1089/hum.2013.161] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Beta-defensins, small antimicrobial peptides, are involved in host immune responses to tumors. In this study, we used beta-defensin 2 (BD2) to explore the possible role of beta-defensins in cancer gene therapy. A recombinant plasmid expressing a secretable form of BD2 was constructed. The biological activities of BD2 in immature dendritic cells (iDCs) were tested in vitro and in vivo. The antitumor effects were investigated in three established tumor models. The secreted BD2 was detected and exhibited chemotactic activity in iDCs both in vitro and in vivo. Recruitment and activation of iDCs in tumor niches resulted in significant tumor growth inhibition. Adoptive transfer of splenocytes and depletion of immune cell subsets revealed that CD8(+) T lymphocyte responses mediated the increased tumor inhibition. Furthermore, we also found that chemotactic and maturation-inducing activities in iDCs in tumor milieu contributed to enhanced local antitumor effects. Our study indicates that gene therapy with BD2 can mediate specific antitumor immunity and augment local antitumor effects. Our study also suggested that beta-defensins may merit further exploration for cancer immunotherapy as promising immunogenes.
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Affiliation(s)
- Dan Li
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu 610042, P.R. China
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Aspord C, Leccia MT, Charles J, Plumas J. Plasmacytoid Dendritic Cells Support Melanoma Progression by Promoting Th2 and Regulatory Immunity through OX40L and ICOSL. Cancer Immunol Res 2013; 1:402-15. [DOI: 10.1158/2326-6066.cir-13-0114-t] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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48
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Arab S, Mojarrad M, Motamedi M, Mirzaei R, Modarressi MH, Hadjati J. Tumour regression induced by co-administration of MIP-3α and CpG in an experimental model of colon carcinoma. Scand J Immunol 2013; 78:28-34. [PMID: 23672351 DOI: 10.1111/sji.12058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 03/25/2013] [Indexed: 01/19/2023]
Abstract
CCL20/macrophage inflammatory protein-3α (MIP-3α) represents one of the potent chemoattractive proteins for dendritic cells (DCs). Herein, we investigated whether in vivo genetic modification of tumour cells aimed at intratumoural production of MIP-3α might lead to accumulation of DCs in tumour tissue. Mice injected with CT26, received recombinant adenovirus (Ad) vectors (AdMIP-3α) expressing MIP-3α protein. This was complemented by injections of CpG. Interestingly, MIP-3α gene therapy combined with CpG injections resulted in specific cytotoxicity. This was associated with significant suppression of tumour growth rate. These findings demonstrate the potential of strategies that utilize in vivo overexpression of chemokines.
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Affiliation(s)
- S Arab
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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49
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Domingos-Pereira S, Decrausaz L, Derré L, Bobst M, Romero P, Schiller JT, Jichlinski P, Nardelli-Haefliger D. Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice. Mucosal Immunol 2013; 6:393-404. [PMID: 22968420 PMCID: PMC3573262 DOI: 10.1038/mi.2012.83] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ~fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.
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Affiliation(s)
- Sonia Domingos-Pereira
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Loane Decrausaz
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Laurent Derré
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Martine Bobst
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Pedro Romero
- Ludwig Center for Cancer, Research of the University of Lausanne, CH-1011 Lausanne, Switzerland
| | - John T. Schiller
- Laboratory of Cellular Oncology, National Cancer Institute, NIH Bethesda, MD, USA
| | - Patrice Jichlinski
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Denise Nardelli-Haefliger
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
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Aspord C, Leccia MT, Salameire D, Laurin D, Chaperot L, Charles J, Plumas J. HLA-A*0201 + Plasmacytoid Dendritic Cells Provide a Cell-Based Immunotherapy for Melanoma Patients. J Invest Dermatol 2012; 132:2395-2406. [DOI: 10.1038/jid.2012.152] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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