title: Restoring anti-tumor functions of T cells via nanoparticle-mediated immune checkpoint modulation.
abstract: The core purpose of cancer immunotherapy is the sustained activation and expansion of the tumor specific T cells, especially tumor-infiltrating cytotoxic T lymphocytes (CTLs). Currently, one of the main foci of immunotherapy involving nano-sized carriers is on cancer vaccines and the role of professional antigen presenting cells, such as dendritic cells (DCs) and other phagocytic immune cells. Besides the idea that cancer vaccines promote T cell immune responses, targeting immune inhibitory pathways with nanoparticle delivered regulatory agents such as small interfering RNA (siRNA) to the difficultly-transfected tumor-infiltrating T cells may provide more information on the utility of nanoparticle-mediated cancer immunotherapy. In this study, we constructed nanoparticles to deliver cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)-siRNA (NPsiCTLA-4) and showed the ability of this siRNA delivery system to enter T cells both in vitro and in vivo. Furthermore, T cell activation and proliferation were enhanced after NPsiCTLA-4 treatment in vitro. The ability of direct regulation of T cells of this CTLA-4 delivery system was assessed in a mouse model bearing B16 melanoma. Our results demonstrated that this nanoparticle delivery system was able to deliver CTLA-4-siRNA into both CD4(+) and CD8(+) T cell subsets at tumor sites and significantly increased the percentage of anti-tumor CD8(+) T cells, while it decreased the ratio of inhibitory T regulatory cells (Tregs) among tumor infiltrating lymphocytes (TILs), resulting in augmented activation and anti-tumor immune responses of the tumor-infiltrating T cells. These data support the use of potent nanoparticle-based cancer immunotherapy for melanoma.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, PR China.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Li
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, PR China.
authors.forename: Cong-Fei
authors.initials: CF
authors.lastname: Xu
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Song
authors.initials: S
authors.lastname: Shen
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, PR China.
authors.forename: Xiao-Jiao
authors.initials: XJ
authors.lastname: Du
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China. Electronic address: xiajx@ustc.edu.cn.
authors.forename: Jin-Xing
authors.initials: JX
authors.lastname: Xia
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Zhu
authors.affiliation: CAS Center for Excellence in Nanoscience, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230027, PR China; Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, PR China; Innovation Center for Cell Signaling Network, University of Science & Technology of China, Hefei, Anhui 230027, PR China. Electronic address: jwang699@ustc.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007773:Lactates / Q000737:chemistry; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory
chemical_list: D060908:CTLA-4 Antigen; D007773:Lactates; D034741:RNA, Small Interfering; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols
keywords: Cancer immunotherapy; Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4); Nanoparticle; Tumor-infiltrating T cells