Mucosal-Associated Invariant T (MAIT) Cell Dysfunction and PD-1 Expression in Prostate Cancer: Implications for Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Despite an abundance of prostate-specific antigens, immunotherapies have yet to become a standard of care, potentially limited by T-cell dysfunction. Up to 10% of human circulating T-cells, and a significant fraction in the urogenital tract, are mucosal-associated invariant T (MAIT) cells. MAIT cells express stereotyped T-cell receptors that recognize riboflavin metabolites derived from microbes presented by MR-1. We evaluated the number, phenotype and function of circulating MAIT cells, alongside two other innate-like T (ILT) -cell subsets, in men with prostate cancer and age- and sex-matched controls. MAIT cells in men with prostate cancer circulated at similar frequencies to controls, but their cytokine production and proliferation was impaired. In contrast, the function of two other ILT-cell populations (natural killer T-cells and Vγ9Vδ2 T-cells) was not impaired. In both patients and controls, MAIT cells expressed high levels of the immune checkpoint molecule PD-1 at rest, while upregulation of PD-1 in response to the MR-1 ligand 5-amino-6D-ribitylaminouracil (5-A-RU) was greater in patients. 5-A-RU also induced upregulation of PD-L1 and -L2 RNA in primary mononuclear cells. We confirmed that circulating MAIT cell number and function were preserved before and during anti-PD1 therapy with pembrolizumab in a cohort of patients with melanoma. In vitro, 5-A-RU enhanced mononuclear cell cytotoxicity against the PD-L1 positive prostate cancer cell line PC3 in an MR-1-dependent manner. Addition of pembrolizumab enhanced this cytotoxicity, and was associated with increased MAIT cell expression of CD107a and IFN-γ. We conclude that prostate cancer is associated with MAIT-cell dysfunction, and that this might be overcome through the application of potent MR-1 ligands with PD-1 blockade. These findings may have implications for the development of cancer immunotherapies that exploit MAIT cells.

An unusual case of spontaneous obstructive thrombus complicating rheumatic mitral stenosis.

We describe a rare case of native mitral valve thrombosis in a patient with rheumatic mitral valve disease without predisposing thrombophilia. The patient presented in heart failure with a new diagnosis of mitral stenosis. After a period of intravenous diuresis there was a sudden cardiovascular collapse. Trans-oesophageal echocardiogram identified an atrial mass obstructing the mitral valve. The patient proceeded to emergent mitral valve replacement. A coagulopathy was identified in the form of thrombus-induced disseminated intravascular coagulation (DIC). Mitral valve thrombosis is a rare cause of morbidity and mortality in rheumatic heart disease and is not readily identifiable on transthoracic echocardiography.

Non-Invasive Detection of Anaemia Using Digital Photographs of the Conjunctiva.

BACKGROUND AND AIMS: Anaemia is a major health burden worldwide. Although the finding of conjunctival pallor on clinical examination is associated with anaemia, inter-observer variability is high, and definitive diagnosis of anaemia requires a blood sample. We aimed to detect anaemia by quantifying conjunctival pallor using digital photographs taken with a consumer camera and a popular smartphone. Our goal was to develop a non-invasive screening test for anaemia. PATIENTS AND METHODS: The conjunctivae of haemato-oncology in- and outpatients were photographed in ambient lighting using a digital camera (Panasonic DMC-LX5), and the internal rear-facing camera of a smartphone (Apple iPhone 5S) alongside an in-frame calibration card. Following image calibration, conjunctival erythema index (EI) was calculated and correlated with laboratory-measured haemoglobin concentration. Three clinicians independently evaluated each image for conjunctival pallor. RESULTS: Conjunctival EI was reproducible between images (average coefficient of variation 2.96%). EI of the palpebral conjunctiva correlated more strongly with haemoglobin concentration than that of the forniceal conjunctiva. Using the compact camera, palpebral conjunctival EI had a sensitivity of 93% and 57% and specificity of 78% and 83% for detection of anaemia (haemoglobin < 110 g/L) in training and internal validation sets, respectively. Similar results were found using the iPhone camera, though the EI cut-off value differed. Conjunctival EI analysis compared favourably with clinician assessment, with a higher positive likelihood ratio for prediction of anaemia. CONCLUSIONS: Erythema index of the palpebral conjunctiva calculated from images taken with a compact camera or mobile phone correlates with haemoglobin and compares favourably to clinician assessment for prediction of anaemia. If confirmed in further series, this technique may be useful for the non-invasive screening for anaemia.