Vitamin D-Dependent Induction of Cathelicidin in Human Macrophages Results in Cytotoxicity Against High Grade B-Cell Lymphoma

Bruns, Heiko; Büttner, Maike; Fabri, Mario; Mougiakakos, Dimitrios; Bittenbring, Joerg Thomas; Pasemann, Shirin; Neumann, Frank; Maurberger, Anna; Kempkes, Bettina; Mackensen, Andréas; Gerbitz, Armin

doi:10.1182/blood.v124.21.4108.4108

Cited by 5 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…B cell chronic lymphocytic leukemia (B-CLL), CTCL with SS, and T cell large granular lymphocytic leukemia (T-LGLL) cells were found to highly express VDR (22,26,27). On the contrary, VDR and CYP27B1 mRNA expression was decreased in tumorassociated macrophages (TAMs) in Burkitt's lymphoma (BL) (28). In a small sampling of only four patients with ALL, none had detectable levels of VDR (29).…”

Section: Vitamin D Receptormentioning

confidence: 99%

“…The primary role of macrophages in cancer progression is less clear as macrophages have the ability to be pro-tumorigenic and anti-tumorigenic, depending on their exerted functions (28). Despite their ability to promote metastasis, macrophages are able to exhibit antibody-dependent cellular cytotoxicity and participate in phagocytosis (28). Some TAMs are unable to execute these cytotoxic functions, leading to escape of cancerous cells.…”

Section: Macrophagesmentioning

confidence: 99%

“…This process may be a result of vitamin D deficiency, which has been demonstrated in BL. Inflammatory M1 macrophages release cathelicidin, an antimicrobial peptide, which kills the B cell lymphoma cells through targeting the BL cell mitochondria (28). However, this process is vitamin D dependent and, interestingly, BL patients have fewer M1 and more M2 macrophages (28).…”

Section: Macrophagesmentioning

confidence: 99%

See 2 more Smart Citations

Vitamin D in hematological disorders and malignancies

Kulling

Olson

et al. 2016

European J of Haematology

View full text Add to dashboard Cite

Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in hematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D 3 , the precursor to the active form of vitamin D, calcitriol, are frequently lower in patients with hematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor, which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal hematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials, and thus, further investigation into the use of these agents in the clinic is warranted. Here, we review the current literature in this field.

show abstract

Section: Vitamin D Receptormentioning

confidence: 99%

Section: Macrophagesmentioning

confidence: 99%

Section: Macrophagesmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin D in hematological disorders and malignancies

Kulling

Olson

et al. 2016

European J of Haematology

View full text Add to dashboard Cite

show abstract

“…As there is a good biological rationale for the role of vitamin D in improving the antibody-dependent antitumor macrophage activity [14], we supplemented vitamin D in patients with low 25(OH)D levels. We chose cholecalciferol (vitamin D3), as this form appears to be more effective than vitamin D2 [18,31].…”

Section: Discussionmentioning

confidence: 99%

“…Antibodymediated cytotoxicity appears to be a major mechanism by which rituximab exerts its B-cell depleting activity [13]. In this context, vitamin D supplementation has been shown to enhance rituximab-mediated cytotoxicity in vitro [14]. It is unknown at present whether these mechanisms are active as well during treatment of lymphoma patients.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D deficiency and supplementation in patients with aggressive B‐cell lymphomas treated with immunochemotherapy

et al. 2017

View full text Add to dashboard Cite

Vitamin D deficiency has been reported to be a negative prognostic factor in elderly patients with aggressive B‐cell lymphomas. In vitro data suggest that vitamin D supplementation may enhance rituximab‐mediated cytotoxicity. We prospectively assessed 25‐hydroxyvitamin D [25(OH)D] levels at diagnosis in a cohort of 155 patients with aggressive B‐cell lymphomas of whom 128 had diffuse large B‐cell lymphoma (DLBCL) not otherwise specified. 25(OH)D levels were deficient (<20 ng/mL) in 105 (67%), insufficient (20–29 ng/mL) in 32 (21%), and normal (≥30 ng/mL) in 18 (12%) patients with a seasonal variation. Patient characteristics associated with lower 25(OH)D levels were poor performance status, overweight, B‐symptoms, elevated LDH, lower albumin and hemoglobin levels. As a result of a change in practice pattern, 116 patients received vitamin D3 (cholecalciferol) supplementation that included a loading phase with daily replacement and subsequent maintenance phase with a weekly dose of 25,000 IU until end of treatment. This resulted in a significant increase in 25(OH)D levels, with normalization in 56% of patients. We analyzed the impact of 25(OH)D levels on event‐free survival in patients treated with Rituximab‐CHOP. 25(OH)D levels below 20 ng/mL at diagnosis and IPI were independently associated with inferior EFS. Moreover, patients with normalized 25(OH)D levels following supplementation showed better EFS than patients with persistently deficient/insufficient 25(OH)D levels. Our study provides the first evidence that achievement of normal 25(OH)D levels after vitamin D3 supplementation is associated with improved outcome in patients with DLBCL and deficient/insufficient 25(OH)D levels when receiving rituximab‐based treatment.

show abstract

TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content

Gunalp,

Helvacı,

Oner

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an inbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known. Methods: Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients. Results: TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content.

show abstract

Vitamin D-Dependent Induction of Cathelicidin in Human Macrophages Results in Cytotoxicity Against High Grade B-Cell Lymphoma

Cited by 5 publications

References 0 publications

Vitamin D in hematological disorders and malignancies

Vitamin D in hematological disorders and malignancies

Vitamin D deficiency and supplementation in patients with aggressive B‐cell lymphomas treated with immunochemotherapy

TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content

Contact Info

Product

Resources

About