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

Detecting Endometrial Cancer by Blood Spectroscopy: A Diagnostic Cross-Sectional Study

Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective and minimally invasive approaches to facilitate the early detection and timely management of endometrial cancer. We analysed blood plasma samples in a cross-sectional diagnostic accuracy study of women with endometrial cancer (n = 342), its precursor lesion atypical hyperplasia (n = 68) and healthy controls (n = 242, total n = 652) using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and machine learning algorithms. We show that blood-based infrared spectroscopy has the potential to detect endometrial cancer with 87% sensitivity and 78% specificity. Its accuracy is highest for Type I endometrial cancer, the most common subtype, and for atypical hyperplasia, with sensitivities of 91% and 100%, and specificities of 81% and 88%, respectively. Our large-cohort study shows that a simple blood test could enable the early detection of endometrial cancer of all stages in symptomatic women and provide the basis of a screening tool in high-risk groups. Such a test has the potential not only to differentially diagnose endometrial cancer but also to detect its precursor lesion atypical hyperplasia—the early recognition of which may allow fertility sparing management and cancer prevention

Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer

Fibroblast Growth Factors (FGFs) have been implicated in malignant transformation, tumor mitogenesis, angiogenesis and chemoresistance. The aim of this study was to determine which FGFs and FGFRs play functional roles in epithelial ovarian cancer. Restriction enzyme analysis of mRNA revealed that transformation was associated with a switch in FGFR2 and FGFR3, from the IIIc to the IIIb isoform. There was widespread expression of FGFs, including FGF7, in all tissues but, FGF3 and FGF19 were expressed by malignant cell lines and cancer tissue but were not present in normal tissue. Using FGFR-specific shRNAi we demonstrated that reductions in FGFR2 inhibited proliferation of ovarian cancer cell lines in vitro (>50%, p < 0.006) and reduced cisplatin IC50 (>60%, p < 0.0001). Cell cycle analysis revealed increased cisplatin sensitivity was associated with increased G2/M arrest and increased apoptosis. FGFR2 shRNAi reduced growth rates of ovarian tumor xenografts by 20% (p < 0.006) and when combined with cisplatin caused a 40% reduction in proliferation rates (p < 0.007). In contrast, RNAi-induced reductions in FGFR1 increased SKOV3 cell numbers, with associated changes in cell cycle but had no effect on ES 2 cells. However, the cisplatin IC50 was reduced (>50%, p < 0.0001) by FGFR1 shRNAi in both cell lines and there was increased apoptosis (46–50%) compared with control cells (35%) (p < 0.004). Together our data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. However, data on the inhibition of FGFR1 suggest that broad spectrum FGFR inhibitors may have unexpected effects on proliferation

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