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The prometastatic microenvironment of the liver.

ABSTRACT: The liver is a major metastasis-susceptible site and majority of patients with hepatic metastasis die from the disease in the absence of efficient treatments. The intrahepatic circulation and microvascular arrest of cancer cells trigger a local inflammatory reaction leading to cancer cell apoptosis and cytotoxicity via oxidative stress mediators (mainly nitric oxide and hydrogen peroxide) and hepatic natural killer cells. However, certain cancer cells that resist or even deactivate these anti-tumoral defense mechanisms still can adhere to endothelial cells of the hepatic microvasculature through proinflammatory cytokine-mediated mechanisms. During their temporary residence, some of these cancer cells ignore growth-inhibitory factors while respond to proliferation-stimulating factors released from tumor-activated hepatocytes and sinusoidal cells. This leads to avascular micrometastasis generation in periportal areas of hepatic lobules. Hepatocytes and myofibroblasts derived from portal tracts and activated hepatic stellate cells are next recruited into some of these avascular micrometastases. These create a private microenvironment that supports their development through the specific release of both proangiogenic factors and cancer cell invasion- and proliferation-stimulating factors. Moreover, both soluble factors from tumor-activated hepatocytes and myofibroblasts also contribute to the regulation of metastatic cancer cell genes. Therefore, the liver offers a prometastatic microenvironment to circulating cancer cells that supports metastasis development. The ability to resist anti-tumor hepatic defense and to take advantage of hepatic cell-derived factors are key phenotypic properties of liver-metastasizing cancer cells. Knowledge on hepatic metastasis regulation by microenvironment opens multiple opportunities for metastasis inhibition at both subclinical and advanced stages. In addition, together with metastasis-related gene profiles revealing the existence of liver metastasis potential in primary tumors, new biomarkers on the prometastatic microenvironment of the liver may be helpful for the individual assessment of hepatic metastasis risk in cancer patients.

SUBMITTER: Vidal-Vanaclocha F

PROVIDER: S-EPMC2654354 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Project description:Liver metastases (LM) remain a major cause of cancer-related death and are a major clinical challenge. LM and the female sex are predictors of a poorer response to immunotherapy but the underlying mechanisms remain unclear. We previously reported on a sexual dimorphism in the control of the tumor microenvironment (TME) of colorectal carcinoma liver metastases (CRCLM) and identified estrogen as a regulator of an immunosuppressive TME in the liver. Here we aimed to assess the effect of estrogen deprivation on the cytokine/chemokine profile associated with CRCLM, using a multiplex cytokine array and the RNAscope technology, and its effects on the innate and adaptive immune responses in the liver. We also evaluated the benefit of combining the selective estrogen-receptor degrader Fulvestrant with immune checkpoint blockade for the treatment of CRCLM. We show that estrogen depletion altered the cytokine/chemokine repertoire of the liver, decreased macrophage polarization, as reflected in reduced accumulation of tumor infiltrating M2 macrophages and increased the accumulation of CCL5+/CCR5+ CD8+ T and NKT cells in the liver TME. Similar results were obtained in a murine pancreatic ductal adenocarcinoma model. Importantly, treatment with Fulvestrant also increased the accumulation of CD8+CCL5+, CD8+CCR5+ T and NK cells in the liver TME and enhanced the therapeutic benefit of anti-PD1 immunotherapy, resulting in a significant reduction in the outgrowth of LM. Taken together, our results show that estrogen regulates immune cell recruitment to the liver and suggest that inhibition of estrogen action could potentiate the tumor-inhibitory effect of immunotherapy in hormone-independent and immunotherapy-resistant metastatic cancer.SignificanceThe immune microenvironment of the liver plays a major role in controlling the expansion of hepatic metastases and is regulated by estrogen. We show that treatment of tumor-bearing mice with an estrogen receptor degrader potentiated an anti-metastatic effect of immunotherapy. Our results provide mechanistic insight into clinical findings and a rationale for evaluating the efficacy of combination anti-estrogen and immunotherapy for prevention and/or treatment of hepatic metastases in female patients.

Project description:Background & aimsWe aim to describe the liver immune microenvironment by analyzing liver biopsies from patients with chronic HBV infection (CHB). Host immune cell signatures and their corresponding localization were characterized by analyzing the intrahepatic transcriptome in combination with a custom multiplex immunofluorescence panel.MethodMatching FFPE and fresh frozen liver biopsies were collected from immune active patients within the open-label phase IV study GS-US-174-0149. RNA-Seq was conducted on 53 CHB liver biopsies from 46 patients. Twenty-eight of the 53 samples had matched FFPE biopsies and were stained with a 12-plex panel including cell segmentation, immune and viral biomarkers. Corresponding serum samples were screened using the MSD Human V-plex Screen Service to identify peripheral correlates for the immune microenvironment.ResultsUsing unsupervised clustering of the transcriptome, we reveal two unique liver immune signatures classified as immune high and immune low based on the quantification of the liver infiltrate gene signatures. Multiplex immunofluorescence analysis demonstrated large periportal lymphoid aggregates in immune high samples consisting of CD4 and CD8 T cells, B cells and macrophages. Differentiation of the high and low immune microenvironments was independent of HBeAg status and peripheral viral antigen levels. In addition, longitudinal analysis indicates that treatment and normalization of ALT correlates with a decrease in liver immune infiltrate and inflammation. Finally, we screened a panel of peripheral biomarkers and identified ICAM-1 and CXCL10 as biomarkers that strongly correlate with these unique immune microenvironments.ConclusionThese data provide a description of immune phenotypes in patients with CHB and show that immune responses are downregulated in the liver following nucleotide analogue treatment. This may have important implications for both the safety and efficacy of immune modulator programs aimed at HBV cure.Lay summaryLiver biopsies from patients with chronic hepatitis B were submitted to RNA-Seq and multiplex immunofluorescence and identified two different liver immune microenvironments: immune high and immune low. Immune high patients showed elevated immune pathways, including interferon signaling pathways, and increase presence of immune cells. Longitudinal analysis of biopsies from treatment experienced patients showed that treatment correlates with a marked decrease in inflammation and these findings may have important implications for both safety and efficacy of immune modulator programs for HBV cure.

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The prometastatic microenvironment of the liver.

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