Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.

Body Composition and Mortality in Coronary Artery Disease With Mild Renal Insufficiency in Chinese Patients.

OBJECTIVE: Obesity is a risk factor for both coronary artery disease (CAD) and chronic renal insufficiency (RI); patients with CAD are prone to obesity and RI. In this study, we try to analyze the effect of body composition on death in CAD patients with mild RI. DESIGN: Retrospective cohort study. SUBJECTS: A total of 1,591 consecutive CAD patients confirmed by coronary angiography were enrolled and met the mild RI criteria by estimated glomerular filtration rate: 60-90 mL/min. MAIN OUTCOME MEASUREMENTS: The influence of body composition on mortality of CAD was detected in different body compositions, including body mass index (BMI), body fat (BF), and lean mass index (LMI). The end points were all-cause mortality. Cox models were used to evaluate the relationship of quintiles of body compositions with all-cause mortality. RESULTS: A survival curve showed that the risk of death was higher in the low BMI group than in the high BMI group (log-rank for overall P = .002); LMI was inversely correlated with risk of death, such that a lower LMI was associated with a higher risk of death (log-rank for overall P < .001). No significant correlation was observed between BF and risk of death. Multifactorial correction show that LMI was still inversely correlated with risk of death (quintile 1: reference; quintile 2: hazard ratio [HR]: 0.49, 95% confidence interval [CI]: 0.26-0.92; quintile 3: HR: 0.35, 95% CI: 0.17-0.70; quintile 4: HR: 0.41, 95% CI: 0.20-0.85; quintile 5: HR: 0.28, 95% CI: 0.12-0.67). CONCLUSION: For CAD patients with mild RI, BMI or BF was unrelated to risk of death, while LMI was inversely correlated with risk of death. A weak "obesity paradox" was observed in this study.

The influence of body composition on renal function in patients with coronary artery disease and its prognostic significance: a retrospective cohort study.

OBJECTIVE: We try to analyse the effect of renal functions on death in CAD patients with different body compositions. METHODS: A retrospective analysis was conducted in 2989 consecutive patients with CAD confirmed by coronary angiography were enrolled and were grouped into two categories: basically preserved renal function (PRF) (eGFR ≥60 ml/min) and obviously reduced renal function (RRF) (eGFR <60 ml/min). The influence of renal insufficiency on mortality of CAD was detected in every tertile of body composition, including body mass index (BMI), body fat (BF) and lean mass index (LMI). The end points were all-cause mortality. RESULTS: The mean follow-up time was 29.1 ± 12.5 months and death events occurred in 271 cases. The percentage of patients with RRF was positively correlated with BF and inversely correlated with the LMI, but no relationship to BMI. The survival curves showed that the risk of death was significantly higher in the RRF patients in all subgroups stratified using BMI, BF, or LMI (log rank test, all p < 0.001). The COX multivariate regression analysis showed that the risk of death was significantly higher in the RRF patients with high BF (HR 1.95, CI 1.25-3.05) and low LMI (HR 1.82, CI 1.19-2.79). Meanwhile, risk of death was significantly higher in RRF patients with a high BMI (HR 2.08, CI 1.22-3.55) or low BMI (HR 1.98, CI 1.28-3.08) but this risk was not significant in patients with a medium BMI (HR 1.12, 0.65-1.94). The subgroup analysis of patients with acute coronary syndrome (ACS) showed similar results. CONCLUSIONS: For patients with CAD, renal insufficiency was positively correlated with BF, inversely correlated with LMI, and unrelated to BMI. The effect of renal insufficiency on the risk of death of CAD was related to body composition.