The utility of poly(γ-glutamic acid) nanoparticles as antigen delivery carriers in dendritic cell-based cancer immunotherapy.

Cytotoxic T-lymphocytes (CTLs) specific for tumor-associated antigens (TAAs) act in the immune surveillance system as major effector cells to eliminate malignant cells. Immunization with TAA-loaded dendritic cells (DCs) has great potential for treating cancer, because DCs are potent antigen-presenting cells capable of inducing antigen-specific CTLs by the primary activation of naive T-lymphocytes. The establishment of a non-cytotoxic and efficient antigen delivery method is required to improve the efficacy of DC-based cancer immunotherapy. We developed biodegradable poly(γ-glutamic acid) nanoparticles (γ-PGA NPs) that can efficiently entrap various proteins as antigen delivery carriers. γ-PGA NPs efficiently delivered entrapped antigenic proteins into DCs without cytotoxicity and presented antigens to DCs via major histocompatibility complex class I and II molecules. Immunization with TAA-loaded DCs using γ-PGA NPs inhibited tumor growth by inducing TAA-specific CTLs. These findings indicate that γ-PGA NPs can function as useful antigen delivery carriers in DC-based cancer immunotherapy.

[1]  M. Albert,et al.  Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs , 1998, Nature.

[2]  Lieping Chen Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity , 2004, Nature Reviews Immunology.

[3]  A. Prescott,et al.  Constitutive macropinocytosis allows TAP‐dependent major histocompatibility compex class I presentation of exogenous soluble antigen by bone marrow‐derived dendritic cells , 1997, European journal of immunology.

[4]  C. Figdor,et al.  Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  M. Akashi,et al.  Nanoparticles built by self-assembly of amphiphilic gamma-PGA can deliver antigens to antigen-presenting cells with high efficiency: a new tumor-vaccine carrier for eliciting effector T cells. , 2008, Vaccine.

[6]  R. Steinman,et al.  Taking dendritic cells into medicine , 2007, Nature.

[7]  Kenneth M. Murphy,et al.  Dendritic cell regulation of TH1-TH2 development , 2000, Nature Immunology.

[8]  P. De Baetselier,et al.  Regulation of Dendritic Cell Numbers and Maturation by Lipopolysaccharide in Vivo , 1996 .

[9]  M. Akashi,et al.  Preparation and characterization of biodegradable nanoparticles based on poly(gamma-glutamic acid) with l-phenylalanine as a protein carrier. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[10]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[11]  R. Vabulas,et al.  Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells , 1998, European journal of immunology.

[12]  R. Steinman,et al.  Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. , 1999, The Journal of clinical investigation.

[13]  D. Sansom,et al.  Integration of CD28 and CTLA‐4 function results in differential responses of T cells to CD80 and CD86 , 2006, European journal of immunology.

[14]  Sebastian Amigorena,et al.  Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells , 1999, Nature Cell Biology.

[15]  M. Akashi,et al.  Development of amphiphilic gamma-PGA-nanoparticle based tumor vaccine: potential of the nanoparticulate cytosolic protein delivery carrier. , 2008, Biochemical and biophysical research communications.

[16]  D. Sansom,et al.  What's the difference between CD80 and CD86? , 2003, Trends in immunology.

[17]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[18]  Ira Mellman,et al.  Dendritic Cells Specialized and Regulated Antigen Processing Machines , 2001, Cell.