Presentation of lipopeptide by dendritic cells induces anti-tumor responses via an endocytosis-independent pathway in vivo

Abstract

Cross-presentation by DCs is the major mechanism by which exogenous antigens activate CTLs. However, the mechanisms of entry and presentation of vaccine peptides by DCs remain unclear. In this study, we determined that the mechanisms of antigen presentation differed between nonlipidated and monopalmitoylated peptide antigens. We found that a nonlipidated long peptide could be taken up by DCs and that the peptide could be colocalized with early endosomes. The uptake of nonlipidated peptides by DCs was inhibited at low temperatures or by the depolymerization of actin filaments or microtubules. In contrast, lipidated peptides were internalized by DCs at low temperatures, and internalization was not inhibited when actin filaments or microtubules were depolymerized. Moreover, lipidated peptide, but not nonlipidated peptide, was internalized by nonphagocytic Jurkat cells. The endosomal/lysosomal and proteasomal degradation pathways were necessary for nonlipidated presentation leading to the activation of CD8(+) T cells, but the proteasomal degradation pathway alone was sufficient to process lipidated peptides for MHC class I presentation. We further found that lipidated peptides could enhance peptide-specific T cell responses in vitro and in vivo and induced stronger antitumor responses than nonlipidated peptides. Taken together, our results demonstrate that DCs present lipidated peptides through an endocytosis-independent pathway to promote strong anti-tumor effects in vivo.

Degradable emulsion as vaccine adjuvant reshapes antigen-specific immunity and thereby ameliorates vaccine efficacy

“…APCs capture antigens in peripheral tissues and then migrate into the draining lymph nodes (LNs) for antigen presentation to lymphocytes15. After antigen uptake, APCs process the protein antigens into peptide epitopes for presentation to T cells and elicit antigen-specific immune responses by regulating costimulatory signals or major histocompatibility complex (MHC) expression16.…”

Mesenchymal Stem Cells Tune the Development of Monocyte-Derived Dendritic Cells Toward a Myeloid-Derived Suppressive Phenotype through Growth-Regulated Oncogene Chemokines

“…Murine BM cells were harvested and differentiated into DCs as previously described (26). BM cells (2 3 10 5 cells/ml) were cultured in RPMI 1640 medium that contained 20 ng/ml recombinant mouse GM-CSF in the presence or absence of the recombinant mouse GRO chemokine.…”

Depletion of tumor-associated macrophages enhances the anti-tumor immunity induced by a Toll-like receptor agonist-conjugated peptide

“…9,10 The mono-palmitoylated peptides derived from viral or tumor-associated antigens are able to effectively elicit antigen-specific cytotoxic T lymphocyte (CTL) activities. [11][12][13][14] However, mono-palmitoylated peptides do not have adjuvant activity but do exhibit increased antigen-cross presentation ability. 13,14 In contrast, di-palmitoylated peptides activate dendritic cells (DCs) and enhance Th1 immune responses through TLR2.…”

“…[11][12][13][14] However, mono-palmitoylated peptides do not have adjuvant activity but do exhibit increased antigen-cross presentation ability. 13,14 In contrast, di-palmitoylated peptides activate dendritic cells (DCs) and enhance Th1 immune responses through TLR2. [15][16][17] Thus, synthetic TLR2 agonist-linked antigens can target and activate DCs to induce effective CTL responses.…”