title: Folate-modified Chitosan Nanoparticles Containing the IP-10 Gene Enhance Melanoma-specific Cytotoxic CD8(+)CD28(+) T Lymphocyte Responses.
abstract: BACKGROUND
  Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) has great potential for the treatment of some malignant cancers. Therefore, augmenting the responses of tumor-specific CTLs is significant for the adoptive immunotherapy of melanoma. This study aimed to investigate the anti-tumor response of a combination therapy employing folate-modified chitosan nanoparticles containing IP-10 (interferon-γ-inducible protein-10) plus melanoma TRP2-specific CD8(+)CD28(+) T cells.
  
  
  METHODS
  We prepared folate-modified chitosan nanoparticles containing the mouse IP-10 gene (FA-CS-mIP-10), and induced melanoma TRP2-specific CD8(+)CD28(+) T cells by co-culturing them with artificial antigen-presenting cells. B16-bearing mice were treated with FA-CS-mIP-10, melanoma TRP2-specific CD8(+)CD28(+) T cells, a combination of both, and the saline control. Tumor volumes and the survival time of mice were recorded. The proportion of myeloid-derived suppressor cells (MDSCs) infiltrating the tumor microenvironment and regulatory T cells (Tregs) in the spleen was analyzed by flow cytometry. We also detected the proliferation and angiogenesis of tumors by immunohistochemistry and apoptosis by TUNEL.
  
  
  RESULTS
  The combination therapy inhibited the progression of melanoma in vivo. Compared with other treatments, it more efficiently inhibited tumor growth and increased the survival time of mice. After treatment with combination therapy, the proportion of MDSCs and Tregs decreased, while the percentage of CXCR3(+)CD8(+) T cells increased. Furthermore, combination therapy inhibited proliferation and promoted apoptosis of tumor cells and significantly inhibited tumor angiogenesis in vivo.
  
  
  CONCLUSIONS
  We describe a novel strategy for improving the anti-tumor response of CD8(+)CD28(+) CTLs by combining them with FA-CS-mIP-10 nanoparticles.
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Jian
authors.initials: J
authors.lastname: He
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Siliang
authors.initials: S
authors.lastname: Duan
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Xia
authors.initials: X
authors.lastname: Yu
authors.affiliation: 2. State Key Laboratory for Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qian
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Sufang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: 3. Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08901, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Xianing
authors.initials: X
authors.lastname: Huang
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Chunhui
authors.initials: C
authors.lastname: Lai
authors.affiliation: 4. Biomedical Polymers Laboratory, Soochow University, Suzhou, Jiangsu 215123, China;
authors.forename: Jinyu
authors.initials: J
authors.lastname: Meng
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Nuo
authors.initials: N
authors.lastname: Zhou
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;; 5. The Department of Immunology, Guangxi Medical University, Nanning, Guangxi 530021, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Lu
authors.affiliation: 1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018106:CD28 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D048271:Chitosan / Q000008:administration & dosage*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D005492:Folic Acid / Q000008:administration & dosage*; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D018106:CD28 Antigens; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D004337:Drug Carriers; D048271:Chitosan; D005492:Folic Acid
keywords: chitosan; cytotoxic T lymphocytes; folate; interferon-γ-inducible protein-10.; melanoma