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for cancer immunotherapies used in the past, such as interleukin-2, was modest due to the ability of tumor cells to avoid elimination by the immune system ( 4 ). Over the past two decades, a tremendous progress has been made in the understanding of
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Introduction Over the past several years, immunotherapy with immune checkpoint inhibitors (ICIs) has become an effective treatment of many malignancies. Immune checkpoints are molecules on the surface of immune cells involved in the regulation
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immunotherapy. Characteristic Patients with HCC Age (years) 47 (34.5–55.5) Sex Male, n (%) 35 (92.1) Female, n (%) 3 (7.9) Drinking Yes 11 (28.9) No 27 (71.1) Smoking Yes
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Introduction Immunotherapy with immune checkpoint inhibitors (CPI’s) has been revolutionising the management of advanced malignancies with their success in improving overall patient survival ( 1 , 2 ). CPI’s are antibodies that block T
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Royal Marsden Hospital, London, UK
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– death) and guide decisions regarding continuation of immunotherapy and need for an immunomodulatory intervention ( Table 1 ). Table 1 CTCAEv5 classification of endocrine dysfunction. CTCAE Toxicity Grade 1 2 3 4 5
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The University of Liverpool, Brownlow Hill, Liverpool, UK
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Introduction Immunotherapy treatment with checkpoint inhibitors (CPI) such as ipilimumab (CTLA-4 inhibitor), nivolumab and pembrolizumab (PD-1 inhibitors) significantly improves prognosis in a number of cancers ( 1 , 2 , 3 ). Combination
School of Nursing, Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Vitamin D has well-documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D system, notably the vitamin D receptor (VDR) and the vitamin D-activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as to attenuate inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported the correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function and increase the risk of inflammatory autoimmune disease.
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the occurrence and development of tumors. For example, a study revealed that inhibiting LRG1 normalizes blood vessels in tumor tissues and enhances the anticancer efficacy of immunotherapy ( 13 ); however, the relationship between LRG1 and thyroid
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
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Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Department of Hepatology and Liver Transplantation, University Hospitals Birmingham (Queen Elizabeth), NHS Hospitals Foundation Trust, Birmingham, UK
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Carcinoid heart disease (CHD) is a consequence of valvular fibrosis triggered by vasoactive substances released from neuroendocrine tumours, classically in those with metastatic disease and resulting in tricuspid and pulmonary valve failure. CHD affects one in five patients who have carcinoid syndrome (CS). Valve leaflets become thickened, retracted and immobile, resulting most often in regurgitation that causes right ventricular dilatation and ultimately, right heart failure. The development of CHD heralds a significantly worse prognosis than those patients with CS who do not develop valvular disease. Diagnosis requires a low threshold of suspicion in all patients with CS, since symptoms occur late in the disease process and clinical signs are difficult to elicit. As a result, routine screening is recommended using the biomarker, N-terminal pro-natriuretic peptide, and regular echocardiography is then required for diagnosis and follow-up. There is no direct medical therapy for CHD, but the focus of non-surgical care is to control CS symptoms, reduce tumour load and decrease hormone levels. Valve surgery improves long-term outcome for those with severe disease compared to medical management, although peri-operative mortality remains at between 10 and 20% in experienced centres. Therefore, care needs to be multidisciplinary at all stages, with clear discussion with the patient and between teams to ensure optimum outcome for these often-complex patients.
School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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Saint Vincent’s Clinical School, UNSW Sydney, Sydney, Australia
SydPath, Saint Vincent’s Hospital, Sydney, Australia
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Gene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, New South Wales, Australia
Faculty of Medicine & Health, The University of Sydney, Camperdown, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
School of Medicine, University of Wollongong, New South Wales, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
Department of Head & Neck Surgery, Liverpool Hospital, Liverpool, New South Wales, Australia
Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
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School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
South West Sydney Clinical School, UNSW Sydney, Sydney, Australia
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-medullary thyroid cancer patients expressing PD-L1 were three times more likely to have a poorer disease-free survival (DFS) than patients who did not have positive PD-L1 expression ( 12 ). Immunotherapies targeting the PD-1/PD-L1 pathway have demonstrated durable
