Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and achieves a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the anti-tumor effects of imatinib. Imatinib therapy activated CD8+ T cells and induced regulatory T cell (T reg) apoptosis within the tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are critical to the anti-tumor effects of imatinib in GIST and concomitant immunotherapy may further improve outcome in human cancers treated with targeted agents.

TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.

Endogenous ligands such as high-mobility group box 1 (HMGB1) and nucleic acids are released by dying cells and bind Toll-like receptors (TLRs). Because TLR9 sits at the interface of microbial and sterile inflammation by detecting both bacterial and endogenous DNA, we investigated its role in a model of segmental liver ischemia-reperfusion (I/R) injury. Mice were subjected to 1 h of ischemia and 12 h of reperfusion prior to assessment of liver injury, cytokines and reactive oxygen species (ROS). Wild-type (WT) mice treated with an inhibitory CpG (iCpG) sequence and TLR9−/− mice had markedly reduced serum alanine aminotransferase (ALT) and inflammatory cytokines following liver I/R. Liver damage was mediated by bone marrow derived cells as WT mice transplanted with TLR9−/− bone marrow were protected from hepatic I/R injury. Injury in WT mice partly depended on TLR9 signaling in neutrophils, which enhanced production of ROS, IL-6, and TNF. In vitro, DNA released from necrotic hepatocytes increased liver non-parenchymal cell (NPC) and neutrophil cytokine secretion via a TLR9-dependent mechanism. Inhibition of both TLR9 and HMGB1 caused maximal inflammatory cytokine suppression in neutrophil cultures and conferred even greater protection from I/R injury in vivo. Conclusions TLR9 serves as an endogenous sensor of tissue necrosis that exacerbates the innate immune response during liver I/R. Combined blockade of TLR9 and HMGB1 represents a clinically relevant, novel approach to limiting I/R injury.

Imatinib reduces tumor cell KIT signaling and causes tumor cell apoptosis, which drives TAMs to shift from M1- to M2-like in mouse and human GIST.

Background: Debate exists regarding outcomes of robot-assisted versus laparoscopic hepatectomy.We reviewed and analyzed major hepatectomies (resection of 3 Couinaud liver segments) performed in a minimally invasive fashion at a single institution.Methods: From 2011 to 2016, 473 major hepatectomy procedures were performed, of which 173 (37%) were performed in a minimally invasive fashion (57 robot-assisted and 116 laparoscopic). Patient demographics, operating statistics and outcomes were analyzed retrospectively.Results: Patients undergoing robot-assisted versus laparoscopic hepatectomy were older (58.1 vs 53.2 years, respectively; p = 0.030), admitted to ICU postoperatively less frequently (43.9% vs 61.2%, respectively; p = 0.043), and readmitted less often within 90 days (7.0% vs 28.5%, respectively; p = 0.001). No significant differences were identified in relation to complications, blood loss, operative times, and length of stay. Conclusion:Robot-assisted is an effective alternative to laparoscopic major hepatectomy for resection of malignant and benign liver lesions. Robotic-assisted offers technical advantages compared to laparoscopic surgery including improved optic visualization, operative dexterity, and ease of dissection and suturing. This experience suggested that the robotic platform was associated with improved outcomes including reduced postoperative ICU admission and 90-day readmission.