Extratumoral PD-1 blockade does not perpetuate obesity-associated inflammation in esophageal adenocarcinoma.

Checkpoint inhibitors, such as anti-PD-1 (Programmed death-1), are transforming cancer treatment for inoperable or advanced disease. As the incidence of obesity-associated malignancies, including esophageal adenocarcinoma (EAC) continues to increase and treatment with checkpoint inhibitors are being FDA approved for a broader range of cancers, it is important to assess how anti-PD-1 treatment might exacerbate pre-existing inflammatory processes at other sites. Outside the EAC tumor, the omentum and liver were found to be enriched with substantial populations of PD-1 expressing T cells. Treatment of omental and hepatic T cells with anti-PD-1 (clone EH12.2H7) did not enhance inflammatory cytokine expression or proliferation, but transiently increased CD107a expression by CD8+ T cells. Importantly, PD-1-expressing T cells are significantly lower in EAC tumor post neoadjuvant chemoradiotherapy, suggesting that combination with specific conventional treatments may severely impair the efficacy of anti-PD-1 immunotherapy. This study provides evidence that systemically administered anti-PD-1 treatment is unlikely to exacerbate pre-existing T cell-mediated inflammation outside the tumor in obesity-associated cancers, such as EAC. Furthermore, our data suggests that studies are required to identify the negative impact of concomitant therapies on PD-1 expression in order to boost overall response rates.

Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver.

The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56(bright) NK cells were Eomes(hi) T-bet(lo) , a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6 (chemokine (C-X-C motif) receptor 6), a marker of tissue residency, which is absent from hepatic CD56(dim) and blood NK cells. Compared to blood populations, these hepatic CD56(bright) NK cells have increased expression of activatory receptors (NKp44, NKp46, and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20-30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment.

CD141⁺ myeloid dendritic cells are enriched in healthy human liver.

BACKGROUND & AIMS: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease. METHODS: During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion. RESULTS: Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs. CONCLUSIONS: Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.