Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Implications of Immunotherapy in Hepatobiliary Tumors.

ABSTRACT: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide. Upon ineligibility for resection, liver transplantation, or locoregional therapies, sorafenib has been the only systemic treatment option of advanced HCC for more than a decade. Immunotherapy is an evolving HCC treatment option that has shown promise in treatment efficacy at an acceptable safety profile during several preceding phase I/II trials. Numerous clinical trials of immune checkpoint inhibitors (ICPIs) alone, in combination of two, or combined with other targeted or locoregional therapies are ongoing. Encouraging results of two-phase III trials testing pembrolizumab or nivolumab versus standard care therapy even resulted in Food and Drug Administration approval for second-line treatment of advanced HCC. ICPIs may open new avenues to the treatment of hepatobiliary tumors, alone or in combination.

SUBMITTER: Gottlieb A

PROVIDER: S-EPMC6597927 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Implications of Immunotherapy in Hepatobiliary Tumors.

Gottlieb Aline A Best Jan J Canbay Ali A

Visceral medicine 20190208 1

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide. Upon ineligibility for resection, liver transplantation, or locoregional therapies, sorafenib has been the only systemic treatment option of advanced HCC for more than a decade. Immunotherapy is an evolving HCC treatment option that has shown promise in treatment efficacy at an acceptable safety profile during several preceding phase I/II trials. Numerous clinical trials of immune checkpoint inhib ...[more]

PMID: 31312646

Similar Datasets

The State of Immunotherapy in Hepatobiliary Cancers.

Project description:Hepatobiliary cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC), are lethal cancers with limited therapeutic options. Curative-intent treatment typically involves surgery, yet recurrence is common and many patients present with advanced disease not amenable to an operation. Immunotherapy represents a promising approach to improve outcomes, but the immunosuppressive tumor microenvironment of the liver characteristic of hepatobiliary cancers has hampered the development and implementation of this therapeutic approach. Current immunotherapies under investigation include immune checkpoint inhibitors (ICI), the adoptive transfer of immune cells, bispecific antibodies, vaccines, and oncolytic viruses. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two ICIs that have demonstrated utility in HCC, and newer immune checkpoint targets are being tested in clinical trials. In advanced CCA and GBC, PD-1 ICIs have resulted in antitumor responses, but only in a minority of select patients. Other ICIs are being investigated for patients with CCA and GBC. Adoptive transfer may hold promise, with reports of complete durable regression in metastatic CCA, yet this therapeutic approach may not be generalizable. Alternative approaches have been developed and promising results have been observed, but clinical trials are needed to validate their utility. While the treatment of hepatobiliary cancers involves unique challenges that these cancers present, the progress seen with ICIs and adoptive transfer has solidified immunotherapy as an important approach in these challenging patients with few other effective treatment options.

| S-EPMC8393650 | biostudies-literature

Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy.

Project description:The major hurdle for cancer vaccines to be effective is posed by tumor immune evasion. Several common immune mechanisms and mediators are exploited by tumors to avoid immune destruction. In an attempt to shed more light on the immunosuppressive environment in uterine tumors, we analyzed the presence of PD-L1, PDL2, B7-H4, indoleamine 2,3-dioxygenase (IDO), galectin- 1, galectin-3, arginase-1 activity and myeloid-derived suppressor cell (MDSC) infiltration. IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemistry. PDL2 was mostly expressed at low levels in these tumors. We found high IDO expression in 21 % of endometrial carcinoma samples and in 14 % of uterine sarcoma samples. For PD-L1 and B7-H4, we found high expression in 92 and 90 % of endometrial cancers, respectively, and in 100 and 92 % of the sarcomas. Galectin-1 and 3 were analyzed in tissue lysates by ELISA, but we did not find an increase in both molecules in tumor lysates compared with benign tissues. We detected expression of galectin-3 by fibroblasts, immune cells and tumor cells in single-cell tumor suspensions. In addition, we noted a highly significant increase in arginase-1 activity in endometrial carcinomas compared with normal endometria, which was not the case for uterine sarcomas. Finally, we could demonstrate MDSC infiltration in fresh tumor suspensions from uterine tumors. These results indicate that the PD-1/PD-L1 interaction and B7-H4 could be possible targets for immune intervention in uterine cancer patients as well as mediation of MDSC function. These observations are another step toward the implementation of inhibitors of immunosuppression in the treatment of uterine cancer patients.

| S-EPMC4024136 | biostudies-literature

Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors.

Project description:Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus' immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.

| S-EPMC7730788 | biostudies-literature

Perspectives on immunotherapy utilization for hepatobiliary cancers in the United States.

Project description: Not available

| S-EPMC7423557 | biostudies-literature

How does the tumor microenvironment play a role in hepatobiliary tumors?

Project description:The tumor microenvironment (TME) is defined as the structural and dynamic network of cellular and non-cellular interactions between malignant cells and the surrounding non-malignant matrix. Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are two of the most challenging gastrointestinal malignancies. Despite clinical advancements in understanding tumor biology and growth of the chemotherapeutic industry, there have been no corresponding improvements in prognosis and overall survival of HCC and PDAC. Both of these cancers have a very intimate relationship with their surrounding environment; the TME is thought to actively participate in initiating and sustaining these malignancies. Individual TME constituents play a vital role in chemoresistance and recurrence after surgery and have been established as independent prognostic factors. This review article will highlight the diverse structural components, key signaling pathways, and extracellular matrices of HCC and PDAC and discuss their crosstalk with tumor cells to promote growth and metastasis. The article will also summarize the latest laboratory and clinical research based on therapeutic targets identified within the TME of both HCC and PDAC.

| S-EPMC5848044 | biostudies-literature

Immunotherapy Targets in Tumors

Project description:Recent work has shown that cytotoxic T cells play a central role in immune-mediated control of cancers1-3, and monoclonal antibodies that target inhibitory receptors on T cells can induce significant clinical benefit in patients despite advanced disease4-6. However, many of the regulatory pathways that result in loss of T cell function within immunosuppressive tumors remain unknown. Here we show that such regulatory mechanisms can be systematically discovered in vivo in the tumor microenvironment. We devised a pool shRNA screening approach aimed at identifying genes that block the function of tumor-infiltrating CD8 T cells. We postulated that shRNAs targeting key inhibitors would enable robust T cell infiltration and proliferation in tumors, despite multiple inhibitory signals. Candidate shRNAs were discovered by transfer of shRNA-transduced T cells into tumor-bearing mice, followed by deep sequencing to quantify the representation of all hairpins in tumors and lymphoid organs. A subset of shRNAs induced T cell accumulation in tumors but not the spleen, demonstrating feasibility of discovering shRNAs with differential action across tissues. One of the targets was Ppp2r2d, a regulatory subunit of the family of PP2A phosphatases7. Control shRNA-transduced T cells underwent apoptosis upon recognition of melanoma cells, while Ppp2r2d shRNA-transduced T cells accumulated in tumors due to enhanced proliferation and reduced apoptosis. Ppp2r2d shRNAexpressing T cells also significantly delayed tumor growth. This in vivo approach has wide applications to dissect complex immune functions in relevant tissue microenvironments. OT-I derived T cells were transduced with shRNA's and adoptively transferred to B16 tumor bearing mice. Following incubation the T cells were purified from either tumors or spleens. The shRNA's targeted either a control gene (LacZ) or one of 5 selected genes found to regulate the presence of T cells in tumors vs in spleen

2014-03-14 | E-GEOD-53388 | biostudies-arrayexpress

Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy.

Project description:Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles. We determined the expression of human leukocyte antigen (HLA)-A/-B/-C, ?-2-microglobulin (B2M), and T cell inhibitory ligands PD-L1 and CTLA-4 by microarray gene analysis and flow cytometry. We examined HLA-A/-B/-C, B2M, and PD-L1 expression on thirty-six NF1-associated tumor samples by immunohistochemistry, and correlated these with tumoral CD4+, CD8+, FOXP3+, CD56+, and CD45RO+ lymphocytic infiltrates. We evaluated several tumors from a single patient, observing trends of increasing immunogenicity over time, even with disease progression. We observed similarly immunogenic profiles for malignant peripheral nerve sheath tumors (MPNST) and nodular and plexiform neurofibromas, contrasting with diffuse neurofibromas. These studies suggest that while immunotherapies may offer some benefit for MPNST and nodular and plexiform neurofibromas, tumor heterogeneity might pose a significant clinical challenge to this novel therapeutic approach.

| S-EPMC5669868 | biostudies-literature

Hepatobiliary cancers and immunotherapy: where are we now and where are we heading?

Project description:Primary liver cancers are a heterogenous collection of diseases with variable natural histories and treatments. This review article will focus on hepatocellular carcinoma (HCC), intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer, and the use of immune checkpoint inhibitors (ICIs) in their treatment. This will include the currently studied, approved uses as well as the potential future roles of ICIs in the treatment of cancers of the hepatobiliary system through recent updates on ongoing studies and discussion of phase III studies underway. Currently, only two ICIs are approved for use in hepatobiliary cancers: nivolumab and pembrolizumab. First, pembrolizumab was approved for either microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) unresectable, or metastatic solid tumors, including HCC and biliary tract cancer (BTC) in May 2017. After CheckMate-040, nivolumab gained approval in late 2017 in the second-line setting for patients with advanced HCC and Child-Pugh A or B7 liver disease. Pembrolizumab was granted FDA approval in 2018 in the second-line setting after publication of KEYNOTE-224 for patients with advanced HCC and Child-Pugh A liver disease. All three approvals were independent of PD-L1 tumor or immune cell expression. Several other ICIs have been studied in various aspects of these diverse diseases including resectable disease and the advanced, unresectable, or metastatic setting from first-line to later line after failed systemic therapies. Some of these agents are also being assessed in combination with currently utilized tyrosine kinase inhibitors (TKIs) and/or chemotherapy. Lastly, we draw attention to phase III clinical trials in ICIs that are currently recruiting and will be approaching completion in the next 5 years, potentially altering the landscape of treatment in hepatobiliary malignancies for generations to come.

| S-EPMC7061229 | biostudies-literature

Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy.

Project description:T lymphocytes function as major players in antigen-mediated cytotoxicity and have become powerful tools for exploiting the immune system in tumor elimination. Several types of T cell-based immunotherapies have been prescribed to cancer patients with durable immunological response. Such strategies include immune checkpoint inhibitors, adoptive T cell therapy, cancer vaccines, oncolytic virus, and modulatory cytokines. However, the majority of cancer patients still failed to take the advantage of these kinds of treatments. Currently, extensive attempts are being made to uncover the potential mechanism of immunotherapy resistance, and myeloid-derived suppressor cells (MDSCs) have been identified as one of vital interpretable factors. Here, we discuss the immunosuppressive mechanism of MDSCs and their contributions to failures of T cell-based immunotherapy. Additionally, we summarize combination therapies to ameliorate the efficacy of T cell-based immunotherapy.

| S-EPMC8317971 | biostudies-literature

MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia.

Project description:MicroRNAs are a class of small regulatory RNAs that function to modulate protein expression. This control allows for fine-tuning of the cellular phenotype, including regulation of proliferation, cell signaling, and apoptosis; not surprisingly, microRNAs contribute to liver cancer biology. Recent investigations in human liver cancers and tumor-derived cell lines have demonstrated decreased or increased expression of particular microRNAs in hepatobiliary cancer cells. Based on predicted and validated protein targets as well as functional consequences of altered expression, microRNAs with decreased expression in liver tumor cells may normally aid in limiting neoplastic transformation. Conversely, selected microRNAs that are up-regulated in liver tumor cells can promote malignant features, contributing to carcinogenesis. In addition, microRNAs themselves are subject to regulated expression, including regulation by tumor suppressor and oncogene pathways. This review will focus on the expression and function of cancer-related microRNAs, including their intimate involvement in tumor suppressor and oncogene signaling networks relevant to hepatobiliary neoplasia.

| S-EPMC2721015 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data