Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: Implications for hepatic anti-tumour immunity

Kelly, Anna M; Golden-Mason, Lucy; Traynor, O.; Geoghegan, Justin; McEntee, Gerry; Hegarty, John E.; O’Farrelly, Cliona

doi:10.1016/j.cyto.2006.07.019

Cited by 23 publications

(21 citation statements)

References 40 publications

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“…We have hypothesized that some hepatic NK‐cell populations differentiate locally from lymphoid progenitors in the adult human liver . Healthy liver tissue contains a complex cytokine milieu and we have identified cytokines essential of progenitor differentiation and NK‐cell activation including IL‐7, IL‐15, IL‐12, IL‐18, and IL‐2 within healthy liver tissue . As evidenced in the present study, the local microenvironment is also capable of inducing liver specific phenotypical and functional changes in BM‐derived NK cells which traffic to the liver.…”

Section: Discussionsupporting

confidence: 65%

Tissue‐resident Eomes^hi T‐bet^lo CD56^bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

et al. 2016

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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 humanliver-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. Eur. J. Immunol. 2016Immunol. . 46: 2111Immunol. -2120 less cytokines than the CD56 bright population [1,2]. Studies in knockout mice have identified a number of transcription factors essential for the developmental program of NK cells, such as Nfil3, Id2,, as well as the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes) [6,7]. In the bone marrow (BM), T-bet expression is initially repressed, allowing the development of Eomes + NK-cell precursors, with T-bet expression subsequently increased during the final stages of NKcell maturation [6]. While conventional NK cells circulate in the PB, transiting through several organs, significant NK-cell populations also permanently reside in tissues such as the lung, gut, uterus, and liver and may develop there [8]. Among these tissue-resident NK-cell populations, the role of uterine NK cells in successful pregnancy is well described [9]; however, the functions of other heterogeneous tissue-resident NK-cell populations remain largely unknown. Within these tissue microenvironments, it is evident that the developmental, functional, and phenotypic features of NK-cell subsets are poorly characterized compared to their PB counterparts [10]. Keywords: CD56 bright natural killer (NK) cells Human liver Interferon MicroenvironmentThe adult human liver contains a unique and extensive lymphoid repertoire. There is a predominance of innate lymphoid cells including NK cells, NKT cells, mucosal-associated invariant T cells and γδ T cells in the liver, in addition to the presence of conventional CD4 + and CD8 + lymphocytes of ...

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Section: Discussionsupporting

confidence: 65%

Tissue‐resident Eomes^hi T‐bet^lo CD56^bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

et al. 2016

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“…NK cell tolerance in steady-state liver is ensured by the presence of inhibitory receptors for self MHC-I molecules, mainly killer cell immunoglobulin-like receptors (KIR) and CD94/NKG2A [72]. Conventional circulating NK cells (CD56 dim CD16 bright ) are being recruited to the inflamed liver and, along lrNK cells, are activated by cytokines such as IL-2, IL-12, IL-18, IL-15 secreted by hepatocytes and Kupffer cells [73]. Upon activation, NK cells operate rapidly, without the requirement for antigen presentation, by producing cytokines (mainly IFN-γ, TNF-α), chemokines and triggering target cell apoptosis via death-inducing molecules-the FAS receptor and the TNF-Related Apoptosis Inducing Ligand (TRAIL)-and via the release of cytotoxic granules [74].…”

Section: Nk Cellsmentioning

confidence: 99%

Immune-based therapies for hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.

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“…We believe this loss of immunosurveillance is in part driven by the unique tumor microenvironment. The liver microenvironment is dramatically altered in the presence of CRLM (23)(24)(25), and the metabolic changes associated with tumor growth can have profound effects on infiltrating immune cells, especially T and NK cells, which require metabolic reprogramming upon activation (26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis

Harmon

Robinson

Hand

et al. 2019

Cancer Immunology Research

224

170

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Colorectal cancer is the third most common malignancy worldwide, with 1.3 million new cases annually. Metastasis to the liver is a leading cause of mortality in these patients. In human liver, metastatic cancer cells must evade populations of liver-resident natural killer (NK) cells with potent cytotoxic capabilities. Here, we investigated how these tumors evade liver NK-cell surveillance. Tissue biopsies were obtained from patients undergoing resection of colorectal liver metastasis (CRLM, n ¼ 18), from the tumor, adjacent tissue, and distal resection margin. The number and phenotype of liver-resident NK cells, at each site, were analyzed by flow cytometry. Tumorconditioned media (TCM) was generated for cytokine and metabolite quantification and used to treat healthy liverresident NK cells, isolated from donor liver perfusate during transplantation. Liver-resident NK cells were significantly depleted from CRLM tumors. Healthy liver-resident NK cells exposed to TCM underwent apoptosis in vitro, associated with elevated lactate. Tumor-infiltrating liver-resident NK cells showed signs of mitochondrial stress, which was recapitulated in vitro by treating liver-resident NK cells with lactic acid. Lactic acid induced apoptosis by decreasing the intracellular pH of NK cells, resulting in mitochondrial dysfunction that could be prevented by blocking mitochondrial ROS accumulation. CRLM tumors produced lactate, thus decreasing the pH of the tumor microenvironment. Liver-resident NK cells migrating toward the tumor were unable to regulate intracellular pH resulting in mitochondrial stress and apoptosis. Targeting CRLM metabolism provides a promising therapeutic approach to restoring local NK-cell activity and preventing tumor growth.

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Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: Implications for hepatic anti-tumour immunity

Cited by 23 publications

References 40 publications

Tissue‐resident Eomes^hi T‐bet^lo CD56^bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

Tissue‐resident Eomes^hi T‐bet^lo CD56^bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

Immune-based therapies for hepatocellular carcinoma

Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis

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Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: Implications for hepatic anti-tumour immunity

Cited by 23 publications

References 40 publications

Tissue‐resident Eomeshi T‐betlo CD56bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

Tissue‐resident Eomeshi T‐betlo CD56bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

Immune-based therapies for hepatocellular carcinoma

Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis

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Product

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Tissue‐resident Eomes^hi T‐bet^lo CD56^bright NK cells with reduced proinflammatory potential are enriched in the adult human liver

Tissue‐resident Eomes^hi T‐bet^lo CD56^bright NK cells with reduced proinflammatory potential are enriched in the adult human liver