PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB.

The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.

Short-term outcomes after incontinent conduit for gynecologic cancer: comparison of ileal, sigmoid, and transverse colon.

OBJECTIVE: The aim of this study is to estimate the overall rates of significant incontinent conduit-related complications and compare rates between conduit types. METHODS: This was a retrospective review of 166 patients who underwent incontinent urinary diversion from April 1993 through April 2013. Patients were categorized by conduit type-ileal, sigmoid colon, and transverse colon. Significant conduit-related complications were assessed at 30 and 90days after surgery. Significant conduit-related complication was defined as any of the following: ureteral stricture, conduit leak, conduit obstruction, conduit ischemia, ureteral anastomotic leak, stent obstruction requiring intervention via interventional radiology procedure or reoperation, and renal failure. RESULTS: A total of 166 patients underwent formation of an incontinent urinary conduit, most commonly during exenteration for gynecologic malignancy. There were 129 ileal, 11 transverse colon, and 26 sigmoid conduits. The overall significant conduit-related complication rate within 30days was 15.1%. Complication rates for ileal, transverse and sigmoid conduits were 14.7%, 0%, and 23.1%, respectively (Fisher's exact test, p=0.24). By 90days, the Kaplan-Meier estimated rates of significant complications were 21.8% overall, and 22.3%, 0%, and 28.9%, respectively, by conduit type (log-rank test, p=0.19). The most common significant conduit-related complications were conduit or ureteral anastomotic leaks and conduit obstructions. By 1 and 2years following surgery, the Kaplan-Meier estimated overall rate of significant conduit-related complication increased to 26.5% and 30.1%, respectively. CONCLUSIONS: Our study suggests that there are multiple appropriate tissue sites for use in incontinent conduit formation, and surgical approach should be individualized. Most significant conduit-related complications occur within 90days after surgery.