The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium

BACKGROUND: The incidence of endometrial cancer is rising in parallel with the obesity epidemic. Obesity increases endometrial cancer risk and weight loss is protective, but the underlying mechanisms are incompletely understood. We hypothesise that the immune microenvironment may influence susceptibility to malignant transformation in the endometrium. The aim of this study was to measure the impact of obesity and weight loss on the immunological landscape of the endometrium. METHODS: We conducted a prospective cohort study of women with class III obesity (body mass index, BMI ≥ 40 kg/m(2)) undergoing bariatric surgery or medically-supervised low-calorie diet. We collected blood and endometrial samples at baseline, and two and 12 months after weight loss intervention. Serum was analysed for inflammatory markers CRP, IL-6 and TNF-α. Multiplex immunofluorescence was used to simultaneously identify cells positive for immune markers CD68, CD56, CD3, CD8, FOXP3 and PD-1 in formalin-fixed paraffin-embedded endometrial tissue sections. Kruskal–Wallis tests were used to determine whether changes in inflammatory and immune biomarkers were associated with weight loss. RESULTS: Forty-three women with matched serum and tissue samples at all three time points were included in the analysis. Their median age and BMI were 44 years and 52 kg/m(2), respectively. Weight loss at 12 months was greater in women who received bariatric surgery (n = 37, median 63.3 kg) than low-calorie diet (n = 6, median 12.8 kg). There were significant reductions in serum CRP (p = 3.62 × 10(−6), r = 0.570) and IL-6 (p = 0.0003, r = 0.459), but not TNF-α levels, with weight loss. Tissue immune cell densities were unchanged except for CD8+ cells, which increased significantly with weight loss (p = 0.0097, r = −0.323). Tissue CD3+ cell density correlated negatively with systemic IL-6 levels (p = 0.0376; r = −0.318). CONCLUSION: Weight loss is associated with reduced systemic inflammation and a recruitment of protective immune cell types to the endometrium, supporting the concept that immune surveillance may play a role in endometrial cancer prevention

Effect of Oxygen on Developing Retinal Vessels with Particular Reference to the Problem of Retrolental Fibroplasia

THE evidence for regarding an abnormal overgrowth of the developing retinal vessels as the pathological basis of retrolental fibroplasia has been reviewed and discussed in an earlier paper in this issue (Ashton, 1954a). This fundamental dysplasia considered alone appeared to indicate thatthe disease was probably no more than a violent " activation of the normal process of retinal vascularization, so that the narrow confines of the nerve fibre layer could no longer contain the exuberant vaso-formative tissue, which conse-quently burst through the limiting membrane to invade the vitreous and so initiated a train of events terminating in total retinal detachment and the formation of a retrolental fibrous membrane. The stimulus which normally attracts the vessels into the retina is itself unknown, but it has been assumed, in general terms, to be a response to the oxygen demands of the inner layers of the retina, which the choroidal circulation is no longer able to satisfy as the eye develops. If retrolental fibroplasia began simply as an overgrowth of normal vaso-formative tissue, it seemed possible that it might occur in response to a stimulus identical in nature with the normal but excessive in degree, a variation which thus appeared to be related to a disparity between oxygen supply and demand. On such a basis, however, it was difficult if not impossible to reconcile the apparently conflicting theories that retrolental fibroplasia was due t

The Effect of Pre-Operative FOLFOX Chemotherapy in Advanced Colon Cancer on Histopathological Features: Analysis of the International Phase III FOxTROT Trial

Background: Endometrial cancer (EC) has strongest association with obesity of all cancers; a 1.60-fold greater risk is conferred per 5kg/m2 increase in body mass index (BMI). Similarly, surgically induced weight loss reduces risk by up to 81%. It is proposed that this association is related to changes in the microenvironment. Although the immune microenvironment has been previously described in normal and neoplastic endometrium, no study has established if it is altered by weight loss.Methods: Samples from a previous prospective study of morbidly obese patients undergoing bariatric surgery were utilised. 43 patients, ages 24-60, were included with three successive biopsies: at surgery, two-months and 12-months. Bloods were taken to collect further clinical data. Patients were predominantly pre-menopausal (37/43) with mean baseline BMI of 52.2 (SD=7.2). Multiplex immunofluorescence was used to simultaneously identify cells positive for markers CD8, CD68, CD3, FOXP3, PD1 and CD56. Primary outcomes were quantity of cells at each time point, repeated measures correlation with weight loss and with systemic inflammatory markers.results: Mean weight loss over 12-months was 29.2kg (SD=12.6). CD8+ (p=0.015, r=-0.32) cell density increased significantly over the 12-months. There was a significant reduction in inflammatory biomarkers CRP (p=1.38x10-5, r=0.58) and IL-6 (p=0.00082, r=0.46). CD3+ density negatively correlated with IL-6 levels (p=0.0028; r =-0.4896).Conclusion: CD8+ cell density in the endometrium increased with surgical weight loss. CD3+ cell density rose, inverse to the fall in IL-6. This supports previous literature on EC immune microenvironments, suggesting these cells play a protective role in the endometrium. It may suggest the inflammatory state seen in obesity downregulates the immune system, as do tumours. These findings could have clinical impact in the development of prognostic biomarkers in EC or immunotherapy targets