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Concomitant Blockade of A2ar and Ctla-4 by Sirna-Loaded Polyethylene Glycol-Chitosan-Alginate Nanoparticles Synergistically Enhances Antitumor T-Cell Responses Publisher Pubmed



Ghasemichaleshtari M1 ; Kiaie SH2, 3 ; Irandoust M4 ; Karami H5 ; Nabi Afjadi M6 ; Ghani S7 ; Aghaei Vanda N4 ; Ghaderi Sede MJ8 ; Ahmadi A9 ; Masjedi A4 ; Hassannia H10 ; Atyabi F11 ; Hojjatfarsangi M12 ; Namdar A13 Show All Authors
Authors
  1. Ghasemichaleshtari M1
  2. Kiaie SH2, 3
  3. Irandoust M4
  4. Karami H5
  5. Nabi Afjadi M6
  6. Ghani S7
  7. Aghaei Vanda N4
  8. Ghaderi Sede MJ8
  9. Ahmadi A9
  10. Masjedi A4
  11. Hassannia H10
  12. Atyabi F11
  13. Hojjatfarsangi M12
  14. Namdar A13
  15. Ghalamfarsa G14
  16. Jadidiniaragh F15, 16
Show Affiliations
Authors Affiliations
  1. 1. Department of Clinical Biochemistry, School of Medicine, Babol University of Medical Sciences, Babol, Mazandaran, Iran
  2. 2. Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
  3. 3. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
  4. 4. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  5. 5. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
  6. 6. Department of Biochemistry, Faculty of Biological Sciences, University of Tarbiat Modares, Tehran, Iran
  7. 7. Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  8. 8. Department of Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, Huntsville, AL, United States
  10. 10. Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
  11. 11. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  12. 12. Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
  13. 13. Department of Oncology, Cross Cancer Institute, The University of Alberta, Edmonton, AB, Canada
  14. 14. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  15. 15. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  16. 16. Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Source: Journal of Cellular Physiology Published:2020


Abstract

Inhibitory immune checkpoint (ICP) molecules are important immunosuppressive factors in a tumor microenvironment (TME). They can robustly suppress T-cell-mediated antitumor immune responses leading to cancer progression. Among the checkpoint molecules, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is one of the critical inhibitors of anticancer T-cell responses. Besides, the expression of adenosine receptor (A2AR) on tumor-infiltrating T cells potently reduces their function. We hypothesized that concomitant silencing of these molecules in T cells might lead to enhanced antitumor responses. To examine this assumption, we purified T cells from the tumor, spleen, and local lymph nodes of CT26 colon cancer-bearing mice and suppressed the expression of A2AR and CTLA-4 using the small interfering RNA (siRNA)-loaded polyethylene glycol-chitosan-alginate (PCA) nanoparticles. The appropriate physicochemical properties of the produced nanoparticles (NPs; size of 72 nm, polydispersive index [PDI] ' 0.2, and zeta potential of 11 mV) resulted in their high efficiency in transfection and suppression of target gene expression. Following the silencing of checkpoint molecules, various T-cell functions, including proliferation, apoptosis, cytokine secretion, differentiation, and cytotoxicity were analyzed, ex vivo. The results showed that the generated nanoparticles had optimal physicochemical characteristics and significantly suppressed the expression of target molecules in T cells. Moreover, a concomitant blockade of A2AR and CTLA-4 in T cells could synergistically enhance antitumor responses through the downregulation of PKA, SHP2, and PP2Aα signaling pathways. Therefore, this combination therapy can be considered as a novel promising anticancer therapeutic strategy, which should be further investigated in subsequent studies. © 2020 Wiley Periodicals LLC
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