To address the challenge of drug accumulation and penetration at the tumor site(s), herein we describe a first-in-class nanocarrier containing 24 copies each of two bioactive peptides (BAPs) genetically fused in frame to the 24 N-termini of a human ferritin H-type construct, named THE-10. The two BAPs are specific for PD-L1 and integrin αVβ3/αVβ5 plus Neuropilin (iRGD) respectively, conferring immune checkpoint blockade and drug-internalization properties. In turn, the THE-10 backbone brings 48 BAPs contiguous for synergism, prolonged blood half-life, and release into the tumor microenvironment upon conditional cleavage of a metalloprotease-sensitive site. Predicted THE-10 multitasking activity was experimentally supported as follows. Size-exclusion chromatography and surface plasmon resonance demonstrated BAP cleavage/release and receptor binding (nanomolar KD). Live-cell/time-lapse imaging demonstrated 4-fold-increased internalization of naked therapeutic antibodies, mirrored by enhanced cytotoxicity of the corresponding Antibody-Drug Conjugate. Slight antitumor effects were observed in vivo by treating immune checkpoint-sensitive syngeneic mouse colorectal model with THE-10 alone. Drug boosting was instead considerable on colorectal and pancreatic tumor allografts when THE-10 was co-administered with both small and large chemotherapeutic agents, outperforming the original iRGD cyclic peptide. Thus, THE-10 may enhance target therapy, chemotherapy and immunotherapy altogether, e.g. it candidates as a multitasking, all-round, antineoplastic therapy booster.
- MeSH
- Ferritins * chemistry genetics pharmacology MeSH
- Immunotherapy * MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nanoparticles * chemistry MeSH
- Drug Carriers * chemistry MeSH
- Antineoplastic Agents pharmacology chemistry MeSH
- Recombinant Proteins chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Dictyosphaerium chlorelloides is a green microalga from the Chlorella clade that produces highly viscous exocellular polysaccharides. The cell wall polysaccharides of this alga have not been studied in detail. In this article, water-soluble polysaccharides from D. chlorelloides biomass were extracted with hot water and purified by preparative chromatography. The composition, structural features and molecular masses of subsequently eluted fractions F1, F2, F3, F4 and F5 (minor) were determined. Three high-yield products F1, F3 and F4 consisted mainly of galactopyranosyl, 2-O-methyl-galactopyranosyl, rhamnopyranosyl and mannopyranosyl units at different proportions, while F2 was rich in glucose. Immunoactivity of these fractions was evidenced in a mixed population of immune cells derived from mice spleens after incubation with polysaccharides by flow cytometry, MTT and Immunospot assays. These fractions, except F2, demonstrated selective immunostimulant activity, and the F1 fraction induced the most potent effect, closely followed by the F3 and F4 fractions. The in vivo mechanism of their action is associated with the activation of innate immunity and shapes the immune response to the Th1 type.
- MeSH
- Adjuvants, Immunologic pharmacology chemistry isolation & purification MeSH
- Cell Wall * chemistry MeSH
- Chlorophyta chemistry MeSH
- Microalgae * chemistry MeSH
- Mice, Inbred BALB C MeSH
- Mice MeSH
- Polysaccharides * pharmacology chemistry isolation & purification MeSH
- Spleen cytology drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Nanoparticles are commonly used in diagnostics and therapy. They are also increasingly being implemented in cancer immunotherapy because of their ability to deliver drugs and modulate the immune system. However, the effect of nanoparticles on immune cells involved in the anti-tumor immune response is not well understood. The study reported here showed that nickel-doped maghemite nanoparticles (FN NP) are differentially cytotoxic to cultured mouse and human cancer cell lines, causing their death without negatively impacting the subsequent anticancer immune response. It also found that FN NP induced cell death in the mouse colorectal cancer cell line CT26 and human prostate cancer cell line PC-3, but not in the human prostate cancer cell line LNCaP. The induced cancer cell death did not affect the phenotype and responsivity of the isolated mouse peritoneal macrophages, or ex vivo-generated mouse bone marrow-derived, or human monocyte-derived dendritic cells. Additionally, the induced cancer cell death did not prevent the ex vivo-generated mouse or human dendritic cells from stimulating lymphocytes and enriching cell cultures with cancer cell-reactive T-cells. In conclusion, this study shows that FN NP could be a valuable platform for targeting cancer cells without causing immunosuppressive effects on the subsequent anticancer immune response.
- MeSH
- PC-3 Cells MeSH
- Dendritic Cells * immunology MeSH
- Immunotherapy * methods MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms immunology therapy MeSH
- Neoplasms immunology therapy MeSH
- Nickel * chemistry immunology MeSH
- Ferric Compounds chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Soft tissue sarcomas are aggressive mesenchymal-origin malignancies. Undifferentiated pleomorphic sarcoma (UPS) belongs to the aggressive, high-grade, and least characterized sarcoma subtype, affecting multiple tissues and metastasizing to many organs. The treatment of localized UPS includes surgery in combination with radiation therapy. Metastatic forms are treated with chemotherapy. Immunotherapy is a promising treatment modality for many cancers. However, the development of immunotherapy for UPS is limited due to its heterogeneity, antigenic landscape variation, lower infiltration with immune cells, and a limited number of established patient-derived UPS cell lines for preclinical research. In this study, we established and characterized a novel patient-derived UPS cell line, JBT19. The JBT19 cells express PD-L1 and collagen, a ligand of the immune checkpoint molecule LAIR-1. JBT19 cells can form spheroids in vitro and solid tumors in immunodeficient nude mice. We found JBT19 cells induce expansion of JBT19-reactive autologous and allogeneic NK, T, and NKT-like cells, and the reactivity of the expanded cells was associated with cytotoxic impact on JBT19 cells. The PD-1 and LAIR-1 ligand-expressing JBT19 cells show ex vivo immunogenicity and effective in vivo xenoengraftment properties that can offer a unique resource in the preclinical research developing novel immunotherapeutic interventions in the treatment of UPS.
- MeSH
- B7-H1 Antigen metabolism MeSH
- Cell Line MeSH
- Immunotherapy MeSH
- Humans MeSH
- Ligands MeSH
- Histiocytoma, Malignant Fibrous * MeSH
- Mice, Nude MeSH
- Mice MeSH
- Sarcoma * pathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Cancer, bacteria, and immunity relationships are much-debated topics in the last decade. Microbiome's importance for metabolic and immunologic modulation of the organism adaptation and responses has become progressively evident, and models to study these relationships, especially about carcinogenesis, have acquired primary importance. The availability of germ-free (GF) animals, i.e., animals born and maintained under completely sterile conditions avoiding the microbiome development offers a unique tool to investigate the role that bacteria can have in carcinogenesis and tumor development. The comparison between GF animals with the conventional (CV) counterpart with microbiome can help to evidence conditions and mechanisms directly involving bacterial activities in the modulation of carcinogenesis processes. Here, we review the literature about spontaneous cancer and cancer modeling in GF animals since the early studies, trying to offer a practical overview on the argument.
- MeSH
- Bacteria MeSH
- Germ-Free Life * MeSH
- Carcinogenesis MeSH
- Microbiota * MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Hot water extract from biomass of heterotrophic mutant green alga Parachlorella kessleri HY1 (Chlorellaceae) was deproteinised, and three polysaccharidic fractions were obtained by preparative chromatography. The low-molecular fraction (1.5 × 104g mol-1) was defined mainly as branched O-2-β-xylo-(1→3)-β-galactofuranan where xylose is partially methylated at O-4. Two high-molecular fractions (3.05 × 105 and 9.84 × 104g mol-1) were complex polysaccharides containing α-l-rhamnan and xylogalactofuranan parts in different ratios. The polysaccharides were well soluble in hot water and, upon cooling, tended to self-segregate. Immunomodulatory activities of the obtained fractions were preliminary tested using ELISA, FACS and ImmunoSpot kits. The polysaccharides increased the TNF-α production in melanoma bearing mice with much higher intensity than in healthy mice. This was in agreement with the FACS results on T and B cells indicating their possibly secondary activation by innate immunity cells.
- MeSH
- B-Lymphocytes drug effects immunology pathology MeSH
- Antigens, CD genetics immunology MeSH
- Chlorophyta chemistry MeSH
- Immunologic Factors chemistry isolation & purification pharmacology MeSH
- Interferon-gamma genetics immunology MeSH
- Interleukin-2 genetics immunology MeSH
- Interleukin-4 genetics immunology MeSH
- Lipopolysaccharides antagonists & inhibitors pharmacology MeSH
- Melanoma immunology pathology MeSH
- Methylation MeSH
- Molecular Weight MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Skin Neoplasms immunology pathology MeSH
- Polysaccharides chemistry isolation & purification pharmacology MeSH
- Primary Cell Culture MeSH
- Gene Expression Regulation drug effects MeSH
- Plant Extracts chemistry MeSH
- Solubility MeSH
- Carbohydrate Sequence MeSH
- T-Lymphocytes drug effects immunology pathology MeSH
- Tumor Necrosis Factor-alpha genetics immunology MeSH
- Water MeSH
- Xylose chemistry isolation & purification MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
New foods and natural biological modulators have recently become of scientific interest in the investigation of the value of traditional medical therapeutics. Glucans have an important part in this renewed interest. These fungal wall components are claimed to be useful for various medical purposes and they are obtained from medicinal mushrooms commonly used in traditional Oriental medicine. The immunotherapeutic properties of fungi extracts have been reported, including the enhancement of anticancer immunity responses. These properties are principally related to the stimulation of cells of the innate immune system. The discovery of specific receptors for glucans on dendritic cells (dectin-1), as well as interactions with other receptors, mainly expressed by innate immune cells (e.g., Toll-like receptors, complement receptor-3), have raised new attention toward these products as suitable therapeutic agents. We briefly review the characteristics of the glucans from mycelial walls as modulators of the immunity and their possible use as antitumor treatments.
- MeSH
- Adjuvants, Immunologic chemistry therapeutic use MeSH
- Agaricales chemistry MeSH
- beta-Glucans chemistry therapeutic use MeSH
- Cell Extracts therapeutic use MeSH
- Dendritic Cells drug effects MeSH
- Lectins, C-Type metabolism MeSH
- Humans MeSH
- Macrophages drug effects immunology MeSH
- Mice MeSH
- Immunity, Innate drug effects MeSH
- Antineoplastic Agents chemistry immunology therapeutic use MeSH
- Signal Transduction immunology MeSH
- Medicine, East Asian Traditional MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
