Artificial human antigen‐presenting cells are superior to dendritic cells at inducing cytotoxic T‐cell responses

Abstract

Peptide recognition through the MHC class I molecule by cytotoxic T lymphocytes (CTLs) leads to the killing of cancer cells. A potential challenge for T-cell immunotherapy is that dendritic cells (DCs) are exposed to the MHC class I-peptide complex for an insufficient amount of time. To improve tumour antigen presentation to T cells and thereby initiate a more effective T-cell response, we generated artificial antigen-presenting cells (aAPCs) by incubating human immature DCs (imDCs) with poly(lactic-co-glycolic) acid nanoparticles (PLGA-NPs) encapsulating tumour antigenic peptides, followed by maturation with lipopolysaccharide. Tumour antigen-specific CTLs were then induced using either peptide-loaded mature DCs (mDCs) or aAPCs, and their activities were analysed using both ELISpot and cytotoxicity assays. We found that the aAPCs induced significantly stronger tumour antigen-specific CTL responses than the controls, which included both mDCs and aAPCs loaded with empty nanoparticles. Moreover, frozen CTLs that were generated by exposure to aAPCs retained the capability to eradicate HLA-A2-positive tumour antigen-bearing cancer cells. These results indicated that aAPCs are superior to DCs when inducing the CTL response because the former are capable of continuously presenting tumour antigens to T cells in a sustained manner. The development of aAPCs with PLGA-NPs encapsulating tumour antigenic peptides is a promising approach for the generation of effective CTL responses in vitro and warrants further assessments in clinical trials.

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“…Considering suboptimal antigen presentation caused by short‐term existence of MHC I‐peptide complexes on mature DCs, Li et al prepared aAPCs by incubating immature DCs with PLGA nanoparticles carrying tumor antigens, which provided continuously endogenous antigens to sustain the MHC class I‐peptide complex formation . The antigenic tumor peptides provided to DCs in a sustained manner contributed to increased antigen presentation to T cells and thus resulted in higher immune response rates.…”

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“…This finding suggests that the increase of neoepitopes (neoantigens) and the enhancement of antigen presentation can be utilized in immunotherapies in combination with immune checkpoint blockade, it could improve patient survival. The results from other studies and ours show that PLGA-nanoparticle-mediated delivery of tumor antigenic peptides effectively induce cytotoxic T cell responses and destroy tumor cells [45][46][47][48]. Virus-based tumor antigen delivery has been also extensively investigated.…”

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“…A detailed method for the generation of aAPCs had been described in our previous publications (Li et al, 2017). Briefly, human imDCs were generated from HLA-A2 positive PBMCs.…”

“…After removing the uninternalized PLGA-NPs by washing with PBS, the imDCs were stained with Hoechst 33342 (Invitrogen, Carlsbad, CA, United States), followed by analysis with a confocal microscope (Leica TCS SP2, Buffalo Grove, IL, United States). To make the end-product of aAPCs, the above human imDCs were further incubated with PLGA-NPs encapsulated SV 95 peptide (PLGA-NPs-SV 95 ) for an hour, followed by maturation with the addition of lipopolysaccharides (LPS, Sigma-Aldrich, St. Louis, MO, United States) at 100 ng/ml for additional 2 days (Ma et al, 2012;Li et al, 2017). These cells were aAPCs, collected on day 7 for further evaluation (e.g., quality control examination), and used for the generation of SV 95 -specific CTLs.…”

“…To improve therapeutic and potent anti-tumor efficacy of tumor antigen specific CTLs, we used human DCs and SV 95 peptide loaded poly (lactic-co-glycolic) acid nanoparticles (PLGA-NPs) to make artificial antigen-presenting cells (aAPCs) and have demonstrated that aAPCs are superior to peptide pulsed DCs when inducing CTL lines due to the aAPCs' capability to continuously present tumor antigens to T cells in a sustained fashion (Li et al, 2017). Because knowledge of the peptides presented on MHC I molecules is fundamental for the development of highly specific T cell-based immunotherapies, we have attempted to further search for novel SV peptide sequences with stronger immunogenicity by artificially changing the peptide sequences based on natural SV 95−1 sequence.…”