Low Levels of Serum and Intracellular Vitamin C in Hospitalized COVID-19 Patients.

Vitamin C is a crucial micronutrient for human immune cell function and has potent antioxidant properties. It is hypothesized that vitamin C serum levels decline during infection. However, the precise mechanisms remain unknown.

No Effect of Vitamin C Administration on Neutrophil Recovery in Autologous Stem Cell Transplantation for Myeloma or Lymphoma: A Blinded, Randomized Placebo-Controlled Trial.

Vitamin C is an important micronutrient for various immune cells. It increases phagocytic cell function and is necessary for T and natural killer (NK) cell development. Patients in need of an autologous hematopoietic stem cell transplantation (HSCT) are often vitamin C-depleted.

Concordance in measurable residual disease result after first and second induction cycle in acute myeloid leukemia: An outcome- and cost-analysis.

Measurable residual disease (MRD) measured using multiparameter flow-cytometry (MFC) has proven to be an important prognostic biomarker in acute myeloid leukemia (AML). In addition, MRD is increasingly used to guide consolidation treatment towards a non-allogenic stem cell transplantation treatment for MRD-negative patients in the ELN-2017 intermediate risk group. Currently, measurement of MFC-MRD in bone marrow is used for clinical decision making after 2 cycles of induction chemotherapy.

Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial.

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach.

NK cell alloreactivity in acute myeloid leukemia in the post-transplant cyclophosphamide era.

Allogeneic hematopoietic stem cell transplantation (alloSCT) for myeloid leukemia remains one of the most effective anti-tumor treatments available, capable of curing an increasingly higher proportion of patients. Alloreactivity generated by T cells has limited efficacy in the early post-transplant period while most patients will relapse within 6 months after transplantation. Prior studies in T cell depleted grafts showed that, with the elimination of T cells, natural killer (NK) cells provide most of the anti-tumor effect in the early post-transplant period.

The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer: A Systematic Review.

Many cancer patients on intensive chemotherapy lack vitamin C. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in those patients. This review assesses the effectiveness and safety of vitamin C administration in cancer.

Influence of Vitamin C on Lymphocytes: An Overview.

Vitamin C or ascorbic acid (AA) is implicated in many biological processes and has been proposed as a supplement for various conditions, including cancer. In this review, we discuss the effects of AA on the development and function of lymphocytes. This is important in the light of cancer treatment, as the immune system needs to regenerate following chemotherapy or stem cell transplantation, while cancer patients are often AA-deficient.

NK cell therapy after hematopoietic stem cell transplantation: can we improve anti-tumor effect?

After decades since the discovery of natural killer (NK) cells as potential effector cells fighting malignantly transformed and virally infected cells, little progress has been made in their clinical application. This yet unrealized therapeutic effect is presumably, at least in part, due to low numbers of functional NK cells that could be obtained from the peripheral blood relative to tumor burden. Our group hypothesized that a relatively small NK cell number to targeted malignant cells is the cause of a lack of clinical effect.

Targeted antigen delivery by an anti-class II MHC VHH elicits focused αMUC1(Tn) immunity.

Unusual patterns of glycosylation on the surface of transformed cells contribute to immune modulation and metastasis of malignant tumors. Active immunization against them requires effective antigen presentation, which is complicated by a lack of access to tumor-specific posttranslational modifications through standard genetic approaches and by the low efficiency of passive antigen sampling. We found that antigen targeted to antigen presenting cells class II MHC products can elicit a robust immune response against MUC1(Tn) bearing a defined tumor-associated glycoform, Tn.

Noninvasive Imaging of Human Immune Responses in a Human Xenograft Model of Graft-Versus-Host Disease.

The immune system plays a crucial role in many diseases. Activation or suppression of immunity is often related to clinical outcome. Methods to explore the dynamics of immune responses are important to elucidate their role in conditions characterized by inflammation, such as infectious disease, cancer, or autoimmunity.

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer.

Purpose: Administration of 5 million alloreactive natural killer (NK) cells after low-dose chemo-irradiation cured mice of 4T1 breast cancer, supposedly dose dependent. We now explored the efficacy of bone marrow as alternative in vivo source of NK cells for anti-breast cancer treatment, as methods for in vitro clinical scale NK cell expansion are still in developmental phases.

Methods: Progression-free survival (PFS) after treatment with different doses of spleen-derived alloreactive NK cells to 4T1-bearing Balb/c mice was measured to determine a dose-response relation.

Pathogen-Associated Molecular Patterns Induced Crosstalk between Dendritic Cells, T Helper Cells, and Natural Killer Helper Cells Can Improve Dendritic Cell Vaccination.

A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can be influenced by a variety of pathogen-associated molecular patterns (PAMPs) and will lead to enhanced CD8(+) effector T cell responses. Specific Pattern Recognition Receptor (PRR) triggering during maturation enables DC to enhance Th1 as well as NK helper cell responses.

Potency of Both Human Th1 and NK Helper Cell Activation is Determined by IL-12p70-Producing PAMP-Matured DCs.

Besides T helper (Th) cells, natural killer (NK) cells have also been described to participate in the shaping of dendritic cell (DC)-mediated adaptive immune responses. At present, it remains unclear to what extent the induction of these NK helper cell immune mechanisms is coupled with Th responses and whether both helper immune responses are induced by the same DC upon specific pathogen recognition receptor (PRR) stimulation. In this study, we demonstrate that maturation of DCs with a cocktail containing FMKp (membrane fragments of Klebsiella pneumoniae) mounts both Th cell and NK cell helper responses in a PRR-triggered dose-dependent manner as determined by the capacity of the helper cells to produce IFN-γ.

Natural killer cells: the secret weapon in dendritic cell vaccination strategies.

In cancer therapy, dendritic cell (DC) vaccination is still being explored. Clinical responses, however, are diverse and there is a lack of immunologic readout systems that correspond with clinical outcome. Only in the minority of patients, T-cell responses correlate with clinical outcome, indicating that other immune cells also gain anticancer activity.

A randomised controlled phase II trial of pre-operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer.

Introduction: Cyclooxygenase-2 (COX-2) is frequently over-expressed in primary breast cancer. In transgenic breast cancer models, over-expression of COX-2 leads to tumour formation while COX-2 inhibition exerts anti-tumour effects in breast cancer cell lines. To further determine the effect of COX-2 inhibition in primary breast cancer, we aimed to identify transcriptional changes in breast cancer tissues of patients treated with the selective COX-2 inhibitor celecoxib.

Inflammation-restraining effects of prostaglandin E2 on natural killer-dendritic cell (NK-DC) interaction are imprinted during DC maturation.

Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance. In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer-dendritic cell (NK-DC) crosstalk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-γ/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation.

T cells fail to develop in the human skin-cell explants system; an inconvenient truth.

Background: Haplo-identical hematopoietic stem cell (HSC) transplantation is very successful in eradicating haematological tumours, but the long post-transplant T-lymphopenic phase is responsible for high morbidity and mortality rates. Clark et al. have described a skin-explant system capable of producing host-tolerant donor-HSC derived T-cells.

Elimination of the chemotherapy resistant subpopulation of 4T1 mouse breast cancer by haploidentical NK cells cures the vast majority of mice.

Metastatic breast cancer is currently incurable despite initial responsiveness, assumingly due to the presence of chemoresistant subpopulations that can be characterized as label retaining cells (LRC). In the 4T1 mouse breast cancer model, we previously achieved cure after Cyclophosphamide and Total Body Irradiation (CY + TBI) followed by haploidentical bone marrow and spleen transplantation (BMSPLT). CY + TBI without transplantation induced only transient impaired tumor growth indicating a critical role of donor immune cells.

Flow cytometry-based assay to evaluate human serum MUC1-Tn antibodies.

Mucin-1 (MUC1) is a heavily O-glycosylated, transmembrane protein that is expressed on the apical surface of most secretory epithelia. In malignantly transformed epithelia, MUC1 has lost its apical distribution, is underglycosylated and is secreted into the circulation. Due to the underglycosylation of MUC1, cancer-specific MUC1-Tn/STn antigens, which are highly immunogenic, become exposed.

Expression of aberrantly glycosylated Mucin-1 in ovarian cancer.

Aims:   Mucin 1 (MUC1) is an important tumour-associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1-glycosylation status of primary ovarian adenocarcinomas and metastatic lesions.

Methods And Results:   Paraffin-embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear-cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry.

Klebsiella pneumoniae-triggered DC recruit human NK cells in a CCR5-dependent manner leading to increased CCL19-responsiveness and activation of NK cells.

Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection.

In vitro-differentiated T/natural killer-cell progenitors derived from human CD34+ cells mature in the thymus.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a treatment option for patients with hematopoietic malignancies that is hampered by treatment-related morbidity and mortality, in part the result of opportunistic infections, a direct consequence of delayed T-cell recovery. Thymic output can be improved by facilitation of thymic immigration, known to require precommitment of CD34(+) cells. We demonstrate that Delta-like ligand-mediated predifferentiation of mobilized CD34(+) cells in vitro results in a population of thymocyte-like cells arrested at a T/natural killer (NK)-cell progenitor stage.