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

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-2K/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.

Prognostic Significance of Potential Immune Checkpoint Member HHLA2 in Human Tumors: A Comprehensive Analysis

“…In addition, the heterogeneity of HHLA2 function was also observed in the co-culture experiment, the T lymphocytes from different donors showed a different response to the HHLA2 protein in cytokine production (17). This contradictory phenomenon is interesting, but also confusing for the further researches on HHLA2 (18–21).…”

Nano-Enhanced Cancer Immunotherapy: Immunology Encounters Nanotechnology

“…First promising in vivo experiments in mice demonstrated that combining aAPC technology with anti-PD-1 ICI immunotherapy synergistically stimulated antigen-specific proliferation of cytotoxic T cells, delayed murine melanoma growth, and extended survival, while either treatment alone had no effect [ 83 ]. Equally, injection of aAPC particles loaded with both IL-2 and anti-CTLA-4 outperformed conventional single-release aAPCs, efficiently promoted sustained ICI and IL-2 release as well as antigen-specific T cell activation and expansion, and inhibited tumor growth in a murine melanoma model [ 110 ]. To make aAPCs even more versatile, Zhang and colleagues developed a multipotent artificial antigen-presenting cell (MaAPC) [ 111 ].…”

Engineering Targeting Materials for Therapeutic Cancer Vaccines

“…In this context, it has been additionally shown that more sustained release of cytokines elicits a stronger immune response. Lastly, these aAPC platforms have also been used to deliver immunosuppressive blocking antibodies and showed promising results in delayed tumor growth (Eggermont et al, 2014;Zhang et al, 2017a).…”