Adipose tissue inflammation contributes to obesity-induced insulin resistance. However, increasing evidence shows that high BMI (obesity) is not an accurate predictor of poor metabolic health in individuals. The molecular mechanisms regulating the metabolically activated M1 macrophage phenotype in the adipose tissues leading to insulin resistance remain largely unknown. Although the Janus Kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling in myeloid cells are known to promote the M2 phenotype in tumors, we demonstrate here that the Jak2/Stat3 pathway amplifies M1-mediated adipose tissue inflammation and insulin resistance under metabolic challenges. Ablating Jak2 in the myeloid compartment reduces insulin resistance in obese mice, which is associated with a decrease in infiltration of adipose tissue macrophages (ATMs). We show that the adoptive transfer of Jak2-deficient myeloid cells improves insulin sensitivity in obese mice. Furthermore, the protection of obese mice with myeloid-specific Stat3 deficiency against insulin resistance is also associated with reduced tissue infiltration by macrophages. Jak2/Stat3 in the macrophage is required for the production of pro-inflammatory cytokines that promote M1 macrophage polarization in the adipose tissues of obese mice. Moreover, free fatty acids (FFAs) activate Stat3 in macrophages, leading to the induction of M1 cytokines. Silencing the myeloid cell Stat3 with an in vivo siRNA targeted delivery approach reduces metabolically activated pro-inflammatory ATMs, thereby alleviating obesity-induced insulin resistance. These results demonstrate Jak2/Stat3 in myeloid cells is required for obesity-induced insulin resistance and inflammation. Moreover, targeting Stat3 in myeloid cells may be a novel approach to ameliorate obesity-induced insulin resistance.

To develop a novel nomogram to improve the preoperative diagnosis of pathological grade of upper tract urothelial carcinoma (UTUC). Retrospective study was conducted with 245 patients with UTUC treated by radical nephroureterectomy from 2002 to 2016. Of the cohort, 57.6% received ureteroscopic (URS) biopsy and 35.9% received urine cytology examination. Preoperative clinical characteristics and examination results were collected. Final pathological grade was diagnosed by postoperative pathology. Univariable and multivariable binary logistic regressions were applied to establish a preoperative predictive model for tumor grade, and significant factors were included in the nomogram. The area under curve (AUC) was used to show the predictive efficacy, and the calibration plot was drawn for validation. Of the 245 patients, 72.7% were diagnosed with pathological high-grade disease. Age (odds ratio [OR] = 1.03, P = .039), sessile (OR = 3.86, P = .021), positive urinary cytology (OR = 6.87, P = .035), and biopsy high-grade result (OR = 10.85, P < .001) were independent predictors for pathological high-grade disease. The predictive nomogram containing these factors achieved an AUC of 0.78, which was significantly better than URS biopsy alone (AUC = 0.62, P = .003) in the whole cohort. In the URS biopsy subgroup, the nomogram achieved an AUC of 0.79, better than biopsy alone (AUC = 0.76), but was not statistically significant (P = .431). When the cutoff value of the nomogram was set at 0.64, the sensitivity of detecting a high-grade lesion versus low-grade lesion was 80.3%, better than that of URS biopsy alone (sensitivity = 65.7%). Advanced age, sessile, positive urinary cytology, and biopsy high-grade were independent predictors of pathological high-grade disease in patients with UTUC. A nomogram containing these factors can improve diagnostic accuracy, potentially reducing the risk of “undergrading” by URS biopsy.

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, PARP inhibitor treatment highly increased intracellular PD-L1 accumulation in both ovarian cancer-patient tumor samples and cell lines. We investigated whether intracellular PD-L1 might play a critical role in ovarian cancer progression. Mutating the PD-L1 acetylation site in PEO1 and ID8^Brca1−/− ovarian cancer cells significantly decreased PD-L1 levels and impaired colony formation, which was accompanied by cell cycle G2/M arrest and apoptosis induction. PEO1 and ID8^Brca1−/− tumors with PD-L1 acetylation site mutation also exhibited significantly reduced growth in mice. Furthermore, targeting intracellular PD-L1 with a cell-penetrating antibody effectively decreased ovarian tumor-cell intracellular PD-L1 level and induced tumor-cell growth arrest and apoptosis, as well as enhanced DNA damage and STING activation, both in vitro and in vivo. In conclusion, we have shown the critical role of intracellular PD-L1 in ovarian cancer progression.