title: CD73 specific siRNA loaded chitosan lactate nanoparticles potentiate the antitumor effect of a dendritic cell vaccine in 4T1 breast cancer bearing mice.
abstract: The efficacy of conventional anti-tumor immunotherapeutic approaches is markedly affected by the immunosuppressive microenvironment of tumor. Since adenosine is one of the main orchestra leaders in immunosuppression symphony of tumor, targeting its producing molecules such as CD73 can help to achieve a better clinical outcome following conventional cancer immunotherapeutic approaches. In the present study, we evaluated the efficacy of CD73-specific siRNA-loaded chitosan-lactate nanoparticles (ChLa NPs) in combination with tumor lysate pulsed dendritic cells (DCs) vaccine in treatment of 4T1 (murine derived) breast cancer bearing mice. Our results showed that intravenous administration of CD73-specific siRNA-loaded NPs led to reduced expression of CD73 in tumor cells which was associated with decreased tumor growth and metastasis, and improved mice survival. Furthermore, we found that the mechanism by which combination therapy inhibits tumor growth is in part related to downregulation of regulatory T (Treg), myeloid derived suppressor cells (MDSCs), and tumor associated macrophages, an augmented CTL effector function, improved proliferation status of T cells, increased production of inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17 and reduced levels of IL-10. Moreover, this treatment protocol attenuated the expression and activities of matrix metalloproteinases (MMPs) 2 and 9 which could be associated to the prevention of lung metastasis. In conclusion, our findings indicate that the use of CD73-specific siRNA-loaded NPs provides an immune potentiating function, thereby improves the efficacy of DC based cancer immunotherapy.
authors.affiliation: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Farhad
authors.initials: F
authors.lastname: Jadidi-Niaragh
authors.affiliation: Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1714614411, Iran; Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Atyabi
authors.affiliation: Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1714614411, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Rastegari
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Nasim
authors.initials: N
authors.lastname: Kheshtchin
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Arab
authors.affiliation: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hadi
authors.initials: H
authors.lastname: Hassannia
authors.affiliation: Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ajami
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Mirsanei
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Sima
authors.initials: S
authors.lastname: Habibi
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Farimah
authors.initials: F
authors.lastname: Masoumi
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Farshid
authors.initials: F
authors.lastname: Noorbakhsh
authors.affiliation: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Fazel
authors.initials: F
authors.lastname: Shokri
authors.affiliation: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: hajatij@sina.tums.ac.ir.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Hadjati
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000818:Animals; D001940:Breast / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy; D007167:Immunotherapy / Q000379:methods; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000067492:RNAi Therapeutics / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D034741:RNA, Small Interfering; D019344:Lactic Acid; D048271:Chitosan; D015720:5'-Nucleotidase
keywords: Adenosine; CD73; Cancer; DC vaccine; Nanoparticle; siRNA