1 alpha, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guérin immunotherapy of bladder cancer.
Hsu Jong-Wei,Yin Peng-Nien,Wood Ronald,Messing James,Messing Edward,Lee Yi-Fen
Bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis(TB), has been used and proven to be one of the most effective treatments for non-muscle invasive bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, thereby limiting the improvement of BCG therapy. Vitamin D deficiency has been associated with a high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy. To test this hypothesis, we examined the impact of 1 alpha, 25-dihydroxyvitamin D3 (1,25-VD) on BCG-induced response in BCa cells and macrophage cells. Our data revealed that 1,25-VD promotes BCG-induced interleukin 8 (IL-8) secretion by BCa cells, consequently inducing the migration of macrophage, THP-1. This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody. Furthermore, 1,25-VD increased BCG-induced expression of macrophage markers in THP-1 cell, and enhanced the BCG-induced THP-1 cytotoxicity against low-grade BCa cells. Importantly, a pre-clinical trial using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model revealed that intravesical co-treatment of 1,25-VD with BCG can prolong mice survival. These data demonstrate a novel mechanism by which 1,25-VD promotes BCG-mediated anti-BCa pathways and provides a platform for improving BCG efficacy with combination of 1,25-VD.
Vitamin D deficiency, autoimmunity, and graft-versus-host-disease risk: Implication for preventive therapy.
Benrashid Mona,Moyers Kim,Mohty Mohamad,Savani Bipin N
The majority of patients after allogeneic stem cell transplantation (HSCT) are expected to have vitamin D deficiency early post HSCT due to poor nutritional status and limited sun exposure. The importance of vitamin D in the immune system has been well defined during the past several years, as vitamin D has demonstrated modulatory effects on the immune system through B and T-lymphocyte, macrophage, monocyte, and dendritic cell regulations, which are the effector cells involved in graft-versus-host-disease (GVHD) pathophysiology after HSCT. High-dose early replacement of vitamin D might attenuate autoimmune reactions and decrease severity of GVHD. In this article, we discuss the hypothetical link between early vitamin D deficiency and GVHD and its potential therapeutic role in GVHD and long-term bone loss after HSCT.
Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.
Grover Shilpa,Dougan Michael,Tyan Kevin,Giobbie-Hurder Anita,Blum Steven M,Ishizuka Jeffrey,Qazi Taha,Elias Rawad,Vora Kruti B,Ruan Alex B,Martin-Doyle William,Manos Michael,Eastman Lauren,Davis Meredith,Gargano Maria,Haq Rizwan,Buchbinder Elizabeth I,Sullivan Ryan J,Ott Patrick A,Hodi F Stephen,Rahma Osama E
BACKGROUND:There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS:We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS:The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS:This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.
Vitamin D, autoimmunity and immune-related adverse events of immune checkpoint inhibitors.
Sun Lillian,Arbesman Joshua,Piliang Melissa
Archives of dermatological research
In addition to its quintessential role in bone homeostasis, vitamin D also plays an important role in regulating the immune system. As such, many studies have demonstrated the therapeutic benefit of vitamin D in treating autoimmune diseases. This immunomodulatory activity of vitamin D has recently attracted more attention due to the rapid development of immunotherapies for cancers, including melanoma. Patients on cancer immunotherapies can suffer from immune-related adverse events (irAEs), which can involve any organ system and range from common dermatological reactions to extremely severe cases of fatal myocarditis in metastatic melanoma patients. Since there are currently no effective approaches to predict or prevent irAEs, it is attractive to potentially leverage the intriguing immunomodulatory effects of vitamin D within this context. This review will discuss recent research investigating the possibility of using vitamin D to alleviate autoimmunity and irAEs with the hope of improving outcomes for patients on cancer immunotherapies, especially within the context of dermatology.
The current state of play of rodent models to study the role of vitamin D in UV-induced immunomodulation.
Gorman Shelley,Hart Prue H
Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology
Ultraviolet radiation (UVR) from sunlight is immunomodulatory and the main source of vitamin D for humans. Vitamin D can also regulate adaptive immunity, through mechanisms that involve the induction or activation of regulatory T cells. Similar mechanisms have also been proposed for the induction of regulatory T cells after skin exposure to UVR. Here we discuss the converging and diverging immunoregulatory pathways of UVR and vitamin D, including the molecular pathways for regulatory T cell induction, non-genomic pathways regulated by vitamin D, antimicrobial peptides, skin integrity and potential interactions between vitamin D and other UVR-induced mediators. We then discuss possible in vivo approaches that could be used to demonstrate a direct (or otherwise) role for vitamin D in mediating the immunosuppressive effects of UVR such as the use of dietary vitamin D restriction to induce vitamin D deficiency, gene knockout mice or drugs to block enzymes of vitamin D metabolism. We end with discussion of the epigenetic effects of vitamin D and UVR for immunosuppression.
The role of vitamin D in inflammatory bowel disease: a guide for clinical practice.
Myint Anthony,Sauk Jenny S,Limketkai Berkeley N
Expert review of gastroenterology & hepatology
INTRODUCTION:Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that carries significant morbidity and mortality. Given the need to identify modifiable risk factors to prevent IBD development and to mitigate disease severity, vitamin D has become a major candidate of interest. AREAS COVERED:In this review, we discuss the regulatory role played by vitamin D in intestinal immune homeostasis, updates in the recent literature exploring its role in IBD pathogenesis and established IBD activity. We also discuss societal recommendations on its therapeutic role in maintaining bone health and future directions for studying its role in regulating disease activity. EXPERT OPINION:In contrast to findings from earlier studies suggesting a causal role in IBD, recent findings indicate that vitamin D deficiency may be a sequela rather than a cause of IBD. Additionally, clinical trials exploring vitamin D therapy in reducing disease activity remain inconclusive thus far, with the current evidence best supporting a therapeutic role of vitamin D in bone health. Future studies are needed to clarify the role of vitamin D in IBD development and disease activity and to determine its therapeutic potential for IBD disease activity.
Clinical experience of integrative cancer immunotherapy with GcMAF.
Inui Toshio,Kuchiike Daisuke,Kubo Kentaro,Mette Martin,Uto Yoshihiro,Hori Hitoshi,Sakamoto Norihiro
BACKGROUND:Immunotherapy has become an attractive new strategy in the treatment of cancer. The laboratory and clinical study of cancer immunotherapy is rapidly advancing. However, in the clinical setting, the results of cancer immunotherapy are mixed. We therefore contend that cancer immunotherapy should be customized to each patient individually based on their immune status and propose an integrative immunotherapy approach with second-generation group-specific component macrophage activating factor (GcMAF)-containing human serum. PATIENTS AND METHODS:The standard protocol of our integrative cancer immunotherapy is as follows: i) 0.5 ml GcMAF-containing human serum is administered intramuscularly or subcutaneously once or twice per week for the duration of cancer therapy until all cancer cells are eradicated; ii) hyper T/natural killer (NK) cell therapy is given once per week for six weeks; iii) high-dose vitamin C is administered intravenously twice per week; iv) alpha lipoic acid (600 mg) is administered orally daily; v) vitamin D3 (5,000-10,000 IU) is administered orally daily. RESULTS:By March 2013, Saisei Mirai have treated over 345 patients with GcMAF. Among them we here present the cases of three patients for whom our integrative immunotherapy was remarkably effective. CONCLUSION:The results of our integrative immunotherapy seem hopeful. We also plan to conduct a comparative clinical study.>
The role of vitamin D in head and neck cancer.
Izreig Said,Hajek Michael,Edwards Heather A,Mehra Saral,Sasaki Clarence,Judson Benjamin L,Rahmati Rahmatullah W
Laryngoscope investigative otolaryngology
Objective:Head and neck squamous cell carcinoma (HNSCC) describes a set of malignancies of the head and neck that continue to inflict considerable morbidity and mortality. Because HNSCC often presents at an advanced stage, patients frequently undergo intensive multi-modal therapy with an intent to cure. Vitamin D is a precursor to the biologically active hormone calcitriol which governs bone and calcium physiology that is obtained from diet and UV-B exposure. Vitamin D is known to have pleiotropic effects on health and disease. In this review, we examine the role of vitamin D in cancer with emphasis on HNSCC and discuss potential avenues for further research that might better elucidate the role of vitamin D in the management of HNSCC. Review methods:A review of MEDLINE database indexed literature concerning the role and biology of vitamin D in HNSCC was conducted, with special consideration of recently published work and research involving immunobiology and HNSCC. Conclusions:The available evidence suggests that vitamin D may play a role in protecting against HNSCC, particularly in persons who smoke, although conflicting and limited data exists. Promising initial work encourages the pursuit of further study. Implications for practice:The significant morbidity and mortality that HNSCC brings warrants continued research in available and safe interventions that improve patient outcomes. With the rise of immunotherapy as an effective modality for treatment, continued research of vitamin D as an adjunct in the treatment of HNSCC is supported.
Inflammation and vitamin D: the infection connection.
Mangin Meg,Sinha Rebecca,Fincher Kelly
Inflammation research : official journal of the European Histamine Research Society ... [et al.]
INTRODUCTION:Inflammation is believed to be a contributing factor to many chronic diseases. The influence of vitamin D deficiency on inflammation is being explored but studies have not demonstrated a causative effect. METHODS:Low serum 25(OH)D is also found in healthy persons exposed to adequate sunlight. Despite increased vitamin D supplementation inflammatory diseases are increasing. The current method of determining vitamin D status may be at fault. The level of 25(OH)D does not always reflect the level of 1,25(OH)2D. Assessment of both metabolites often reveals elevated 1,25(OH)2D, indicating abnormal vitamin D endocrine function. FINDINGS:This article reviews vitamin D's influence on the immune system, examines the myths regarding vitamin D photosynthesis, discusses ways to accurately assess vitamin D status, describes the risks of supplementation, explains the effect of persistent infection on vitamin D metabolism and presents a novel immunotherapy which provides evidence of an infection connection to inflammation. CONCLUSION:Some authorities now believe that low 25(OH)D is a consequence of chronic inflammation rather than the cause. Research points to a bacterial etiology pathogenesis for an inflammatory disease process which results in high 1,25(OH)2D and low 25(OH)D. Immunotherapy, directed at eradicating persistent intracellular pathogens, corrects dysregulated vitamin D metabolism and resolves inflammatory symptoms.
Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors.
Stucci Luigia Stefania,D'Oronzo Stella,Tucci Marco,Macerollo Antonella,Ribero Simone,Spagnolo Francesco,Marra Elena,Picasso Virginia,Orgiano Laura,Marconcini Riccardo,De Rosa Francesco,Di Guardo Lorenza,Galli Giulia,Gandini Sara,Palmirotta Raffaele,Palmieri Giuseppe,Queirolo Paola,Silvestris Francesco,
Cancer treatment reviews
The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive. However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed.
Vitamin D: is it important in haematopoietic stem cell transplantation? A review.
Ros-Soto Jose,Anthias Chloe,Madrigal Alejandro,Snowden John A
Bone marrow transplantation
Vitamin D has effects on several body systems, from well-established role in bone metabolism to emerging effects on the immune system. Increasing evidence supports an immunomodulatory effect including inhibition of the pro-inflammatory lymphocyte subsets while enhancing their anti-inflammatory counterpart, in favour of a more tolerogenic status. Vitamin D deficiency is increasingly recognised in association with autoimmune and inflammatory diseases, also with evidence from the field of asthma where vitamin D supplementation may overcome steroid resistance. In the HSCT setting, vitamin D deficiency has been variably associated with increased complications, including graft-versus-host disease (GvHD), with a potential impact on survival outcomes. In this review we provide an overview and critical appraisal of the current literature of the role of vitamin D (and its deficiency) in relation to immunity in both allogeneic and autologous HSCT settings. We conclude that the evidence base is mixed, but a greater understanding of the role of vitamin D in relation to immune reconstitution following HSCT is warranted. Given its potential benefits, its inexpensive cost and favourable side effect profile, consideration of vitamin D levels and its supplementation could be easily incorporated into prospective studies in GvHD, including clinical trials of novel therapeutics, supportive care and biomarkers.