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.

Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma.

The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-ß, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103- DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.

Disentangling the effects of race and socioeconomic factors on liver transplantation rates for hepatocellular carcinoma.

INTRODUCTION: Liver transplantation is the most effective treatment for hepatocellular carcinoma (HCC) in eligible patients, but is not accessed equally by all. We explored the effects of race and socioeconomic factors on transplantation for HCC while controlling for stage, resection status, and transplant candidacy. PATIENTS AND METHODS: All HCC patients, 2003-2013, were retrospectively analyzed using multivariate analysis to explore differences in transplantation rates among cohorts. RESULTS: Of 3078 HCC patients, 754 (24%) were considered transplant eligible. Odds of transplantation were significantly higher for those with commercial insurance (OR = 1.99, 95% CI [1.42, 2.79]) and lower for black patients (OR = 0.55, 95% CI [0.33, 0.91]). Asians were more likely to be resected than white patients with similarly staged tumors and transplant criteria (p < 0.001). Patients not listed for transplantation for non-medical reasons were more likely to be government-insured (p = 0.02) and not white (p = 0.05). No step along the transplantation pathway was identified as the dominant hurdle. DISCUSSION: Patients who are black or government-insured are significantly less likely to undergo transplantation for HCC despite controlling for tumor stage, resection status, and transplant eligibility. Asian patients have higher rates of hepatic resection, but also appear to have lower transplantation rates beyond this effect.