Unknown

Dataset Information

0

An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides.


ABSTRACT: BACKGROUND:Receptors specific for the sugar N-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has been proposed to play an important role in maturation of dendritic cells and initiation of an immune response. In this study, we asked whether a peptide that binds in the GalNAc-binding site of CLEC10A would serve as an effective tool to activate an immune response against ovarian cancer. METHODS:A 12-mer sequence emerged from a screen of a phage display library with a GalNAc-specific lectin. The peptide, designated svL4, and a shorter peptide consisting of the C-terminal 6 amino acids, designated sv6D, were synthesized as tetravalent structures based on a tri-lysine core. In silico and in vitro binding assays were developed to evaluate binding of the peptides to GalNAc-specific receptors. Endotoxin-negative peptide solutions were administered by subcutaneous injection and biological activity of the peptides was determined by secretion of cytokines and the response of peritoneal immune cells in mice. Anti-cancer activity was studied in a murine model of ovarian cancer. RESULTS:The peptides bound to recombinant human CLEC10A with high avidity, with half-maximal binding in the low nanomolar range. Binding to the receptor was Ca2+-dependent. Subcutaneous injection of low doses of peptides into mice on alternate days resulted in several-fold expansion of populations of mature immune cells within the peritoneal cavity. Peptide sv6D effectively suppressed development of ascites in a murine ovarian cancer model as a monotherapy and in combination with the chemotherapeutic drug paclitaxel or the immunotherapeutic antibody against the receptor PD-1. Toxicity, including antigenicity and release of cytotoxic levels of cytokines, was not observed. CONCLUSION:sv6D is a functional ligand for CLEC10A and induces maturation of immune cells in the peritoneal cavity. The peptide caused a highly significant extension of survival of mice with implanted ovarian cancer cells with a favorable toxicity and non-antigenic profile.

SUBMITTER: Eggink LL 

PROVIDER: S-EPMC5905120 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides.

Eggink Laura L LL   Roby Katherine F KF   Cote Robert R   Kenneth Hoober J J  

Journal for immunotherapy of cancer 20180417 1


<h4>Background</h4>Receptors specific for the sugar N-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has  ...[more]

Similar Datasets

| S-EPMC6630963 | biostudies-literature
| S-EPMC9955550 | biostudies-literature
| S-EPMC4372273 | biostudies-literature
| S-EPMC6723090 | biostudies-other
| S-EPMC7409311 | biostudies-literature
2019-08-15 | PXD014718 | Pride
| S-EPMC3005762 | biostudies-literature
| S-EPMC5645638 | biostudies-literature
| S-EPMC6302491 | biostudies-literature
| S-EPMC5423722 | biostudies-literature