PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming.

BACKGROUND AND AIMS: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). APPROACH AND RESULTS: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4+ , PD1+ , Ly6C+ CD44+ phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution. CONCLUSIONS: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4+ T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.

Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis.

Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.

Outcome of Endoscopic Management of Post Living Donor Liver Transplant Anastomotic Strictures.

OBJECTIVE: To evaluate the therapeutic efficacy of endoscopic dilatation of anastomotic stricture (AS). STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Department of Gastroenterology and Hepatology, Shaikh Zayed Hospital, Lahore, Pakistan from November 2016 to November 2017. METHODOLOGY: Patients presenting with anastomotic biliary stricture following living donor liver transplant (LDLT) underwent endoscopic retrograde cholangio-pancreaticography (ERCP) and treatment of their strictures with dilatation with or without stenting. The patients were then followed up to see adequate resolution of stricture and repeat therapeutic ERCP was performed, if required. The patients were labelled as cured if stricture resolution persisted for a period of up to six months following ERCP. RESULTS: Forty-three patients (32 males and 11 females), with post-LDLT AS, who met the inclusion and exclusion criteria were enrolled in the study. Thirty-six (83.7%) patients had a single biliary anastomosis while seven (16.3%) patients had two anastomoses. Ductoplasty was done in 15 (34.9%) of the enrolled patients. Patients with post-LDLT AS required 3.65 +1.15 sessions of ERCP. Plastic type biliary stent was used in seven (16.3%) patients, balloon dilatation alone was done in five (11.6%) patients and combined balloon dilatation and stent placement was performed in 29 (67.4%) patients, and combined graduated dilator and stent placement was performed in two (4.7%) patients. Five (11.6%) patients required rendezvous procedure (whereby a radiologist placed a guidewire percutaneously into the biliary system) as guidewire placement across stricture site was endoscopically unsuccessful. The overall success rate was 88.4%. Mean stent free follow-up was 7.18 +1.38 months. Recurrence of AS was noted in one (2.3%) patient. CONCLUSION: Endoscopic management of post-LDLT AS has an efficacious long-term outcome.