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Cancer Immunology, Immunotherapy

, Volume 66, Issue 9, pp 1229–1241 | Cite as

Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model

  • Lei Zhang
  • Limin Wang
  • Khawar Ali Shahzad
  • Tao Xu
  • Xin Wan
  • Weiya Pei
  • Chuanlai ShenEmail author
Original Article

Abstract

Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2Kb/TRP2-Ig dimer and anti-CD28 onto the surface. Cytokines (activating signal) and antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting tumor growth in a mouse melanoma model, as compared with conventional two-signal aAPCs and IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of tumors and infectious diseases.

Keywords

Artificial antigen-presenting cells PLGA-MPs IL-2 Anti-CTLA-4 Active immunotherapy 

Abbreviations

7-AAD

7-amino-actinomycin D

aAPCs

Artificial antigen-presenting cells

MNPs

Micro- and nanoparticles

MPs

Microparticles

PEI

Polyethylenimine

PLGA

Polylactic-co-glycolic acid

pMHC

Peptide-major histocompatibility complex

TRP2

Tyrosinase-related protein 2

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81172823, 81372448) and the Science and Technology Support Program of Jiangsu Province (BE2012739).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

262_2017_2016_MOESM1_ESM.pdf (945 kb)
Supplementary material 1 (PDF 944 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Microbiology and Immunology, Medical SchoolSoutheast UniversityNanjingPeople’s Republic of China

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