Original Article

Cancer Immunology, Immunotherapy

, Volume 62, Issue 7, pp 1161-1173

First online:

Efficient ex vivo induction of T cells with potent anti-tumor activity by protein antigen encapsulated in nanoparticles

  • Rodney A. RosaliaAffiliated withDepartment of Clinical Pharmacy and Toxicology, Leiden University Medical Center
  • , Ana Luisa SilvaAffiliated withDivision of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden University
  • , Marcel CampsAffiliated withDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center
  • , Ahmed AllamAffiliated withDivision of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden University
  • , Wim JiskootAffiliated withDivision of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden University
  • , Sjoerd H. van der BurgAffiliated withDepartment of Clinical Oncology, Leiden University Medical Center
  • , Ferry OssendorpAffiliated withDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center Email author 
  • , Jaap OostendorpAffiliated withDepartment of Clinical Pharmacy and Toxicology, Leiden University Medical Center

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Abstract

Protein antigen (Ag)-based immunotherapies have the advantage to induce T cells with a potentially broad repertoire of specificities. However, soluble protein Ag is generally poorly cross-presented in MHC class I molecules and not efficient in inducing robust cytotoxic CD8+ T cell responses. In the present study, we have applied poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) which strongly improve protein Ag presentation by dendritic cells (DC) in the absence of additional Toll-like receptor ligands or targeting devices. Protein Ag-loaded DC were used as antigen presenting cells to stimulate T cells in vitro and subsequently analyzed in vivo for their anti-tumor effect via adoptive transfer, a treatment strategy widely studied in clinical trials as a therapy against various malignancies. In a direct comparison with soluble protein Ag, we show that DC presentation of protein encapsulated in plain PLGA-NP results in efficient activation of CD4+ and CD8+ T cells as reflected by high numbers of activated CD69+ and CD25+, interferon (IFN)-γ and interleukin (IL)-2-producing T cells. Adoptive transfer of PLGA-NP-activated CD8+ T cells in tumor-bearing mice displayed good in vivo expansion capacity, potent Ag-specific cytotoxicity and IFN-γ cytokine production, resulting in curing mice with established tumors. We conclude that delivery of protein Ag through encapsulation in plain PLGA-NP is a very efficient and simple procedure to stimulate potent anti-tumor T cells.

Keywords

PLGA OVA Ag cross-presentation Adoptive immunotherapy