Immune Curbing of Cancer Stem Cells by CTLs Directed to NANOG

Cancer stem cells (CSCs) have been identified as the source of tumor growth and disease recurrence. Eradication of CSCs is thus essential to achieve durable responses, but CSCs are resistant to current anti-tumor therapies. Novel therapeutic approaches that specifically target CSCs will, therefore, be crucial to improve patient outcome. Immunotherapies, which boost the body’s own immune system to eliminate cancerous cells, could be an alternative approach to target CSCs. Vaccines of dendritic cells (DCs) loaded with tumor antigens can evoke highly specific anti-tumor T cell responses. Importantly, DC vaccination also promotes immunological memory formation, paving the way for long-term cancer control. Here, we propose a DC vaccination that specifically targets CSCs. DCs loaded with NANOG peptides, a protein required for maintaining stem cell properties, could evoke a potent anti-tumor immune response against CSCs. We hypothesize that the resulting immunological memory will also control newly formed CSCs, thereby preventing disease recurrence

Long Overall Survival After Dendritic Cell Vaccination in Metastatic Uveal Melanoma Patients

Purpose: To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma. Design: Interventional case series. Methods: We analyzed 14 patients with metastatic uveal melanoma treated with dendritic cell vaccination. Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase. The main outcome measures were safety, immunologic response, and overall survival. Results: Tumor-specific immune responses were induced with dendritic cell vaccination in 4 (29%) of14 patients. Dendritic cell-vaccinated patients showed a median overall survival with metastatic disease of 19.2months, relatively long compared with that reported in the literature. No severe treatment-related toxicities (common toxicity criteria grade 3 or 4) were observed. Conclusions: Dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell-based immunotherapy is potent to enhance the host's antitumor immunity against uveal melanoma in approximately one third of patients. Compared with other prospective studies with similar inclusion criteria, dendritic cell vaccination may be associated with longer than average overall survival in patients with metastatic uveal melanoma

A Comparative Study of the T Cell Stimulatory and Polarizing Capacity of Human Primary Blood Dendritic Cell Subsets

Dendritic cells (DCs) are central players of immune responses; they become activated upon infection or inflammation and migrate to lymph nodes, where they can initiate an antigen-specific immune response by activating naive T cells. Two major types of naturally occurring DCs circulate in peripheral blood, namely, myeloid and plasmacytoid DCs (pDCs). Myeloid DCs (mDCs) can be subdivided based on the expression of either CD1c or CD141. These human DC subsets differ in surface marker expression, Toll-like receptor (TLR) repertoire, and transcriptional profile, suggesting functional differences between them. Here, we directly compared the capacity of human blood mDCs and pDCs to activate and polarize CD4 + T cells. CD141 + mDCs show an overall more mature phenotype over CD1c + mDC and pDCs; they produce less IL-10 and more IL-12 than CD1c + mDCs. Despite these differences, all subsets can induce the production of IFN-in naive CD4 + T cells. CD1c + and CD141 + mDCs especially induce a strong T helper 1 profile. Importantly, naive CD4 + T cells are not polarized towards regulatory T cells by any subset. These findings further establish all three human blood DCs-despite their differences-as promising candidates for immunostimulatory effectors in cancer immunotherapy

Проблемы увеличения продуктивности АПК в Украине и пути повышения его потенциала

Целью статьи является изучение причин снижения показателей продуктивности в агропромышленном комплексе и путей повышения продуктивности сельскохозяйственных культур

The clinical application of cancer immunotherapy based on naturally circulating dendritic cells

Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation. One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished, plasmacytoid DCs, CD141+ and CD1c+ myeloid/conventional DCs, each with distinct functional characteristics. In completed clinical trials, either CD1c+ myeloid DCs or plasmacytoid DCs were administered and showed encouraging immunological and clinical outcomes. Currently, also the combination of CD1c+ myeloid and plasmacytoid DCs as well as the intratumoral use of CD1c+ myeloid DCs is under investigation in the clinic. Isolation and culture strategies for CD141+ myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future prospects of natural DC-based immunotherapy

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk

Maturation of monocyte-derived dendritic cells with Toll-like receptor 3 and 7/8 ligands combined with prostaglandin E2 results in high interleukin-12 production and cell migration

Dendritic cells (DC) are professional antigen-presenting cells of the immune system that play a key role in regulating T cell-based immunity. In vivo, the capacity of DC to activate T cells depends on their ability to migrate to the T cell areas of lymph nodes as well as on their maturation state. Depending on their cytokine-secreting profile, DC are able to skew the immune response in a specific direction. In particular, IL-12p70 producing DC drive T cells towards a T helper 1 type response. A serious disadvantage of current clinical grade ex vivo generated monocyte-derived DC is the poor IL-12p70 production. We have investigated the effects of Toll-like receptor (TLR)-mediated maturation on ex vivo generated human monocyte-derived DC. We demonstrate that in contrast to cytokine-matured DC, DC matured with poly(I:C) (TLR3 ligand) and/or R848 (TLR7/8 ligand) are able to produce vast amounts of IL-12p70, but exhibit a reduced migratory capacity. The addition of prostaglandin E2 (PGE2) improved the migratory capacity of TLR-ligand matured DC while maintaining their IL-12p70 production upon T cell encounter. We propose a novel clinical grade maturation protocol in which TLR ligands poly(I:C) and R848 are combined with PGE2 to generate DC with both high migratory capacity and IL-12p70 production upon T cell encounter

NAD(P)H:quinone oxidoreductase 1 expression in multiple sclerosis lesions

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), marked by infiltration of monocyte-derived macrophages in the brain parenchyma. Macrophages contribute to disease pathology by secretion of inflammatory mediators, such as reactive oxygen species (ROS). ROS are involved in various processes underlying MS pathology, including monocyte migration across the blood-brain barrier, phagocytosis and degradation of myelin, axonal degeneration, and oligodendrocyte damage. High concentrations of ROS cause oxidative stress, which induces transcriptional activation of phase II detoxification enzymes, such as the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1). Since NQO1 expression may act as an indicator of oxidative stress and knowledge about the cellular distribution pattern of NQO1 in MS brains is lacking, we examined the expression of NQO1 in various well-characterized MS lesions. Here, we show for the first time that NQO1 is highly upregulated in active and chronic active MS lesions, particularly in hypertrophic astrocytes and myelin-laden macrophages. We hypothesize that increased NQO1 expression may reflect an endogenous defense response against ROS-mediated cellular toxicity. Compounds that induce the production of endogenous antioxidant enzymes, such as NQO1, may be potential targets for future treatment strategies in MS

CD1 and Major Histocompatibility Complex II Molecules Follow a Different Course during Dendritic Cell Maturation

The maturation of dendritic cells is accompanied by the redistribution of major histocompatibility complex (MHC) class II molecules from the lysosomal MHC class II compartment to the plasma membrane to mediate presentation of peptide antigens. Besides MHC molecules, dendritic cells also express CD1 molecules that mediate presentation of lipid antigens. Herein, we show that in human monocyte-derived dendritic cells, unlike MHC class II, the steady-state distribution of lysosomal CD1b and CD1c isoforms was unperturbed in response to lipopolysaccharide-induced maturation. However, the lysosomes in these cells underwent a dramatic reorganization into electron dense tubules with altered lysosomal protein composition. These structures matured into novel and morphologically unique compartments, here termed mature dendritic cell lysosomes (MDL). Furthermore, we show that upon activation mature dendritic cells do not lose their ability of efficient clathrin-mediated endocytosis as demonstrated for CD1b and transferrin receptor molecules. Thus, the constitutive endocytosis of CD1b molecules and the differential sorting of MHC class II from lysosomes separate peptide- and lipid antigen-presenting molecules during dendritic cell maturation