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Genetic/epigenetic alteration and tumor immune microenvironment in intrahepatic cholangiocarcinoma: Transforming the immune microenvironment with molecular targeted agents

LIVER CANCER (2023)

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Summary: This study characterizes the immunogenomic contexture of hepatocellular carcinoma (HCC) and defines inflamed and non-inflamed tumors. Two distinct patterns of CTNNB1 are associated with differential immune evasion and may help predict immune response in HCC.

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Article Gastroenterology & Hepatology

Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications

Miguel A. Martin-Serrano et al.

Summary: We present a comprehensive stratification of iCCA based on the tumor microenvironment (TME). The tumor is divided into five stable STIM classes, including 35% inflamed and 65% non-inflamed profiles. The inflamed classes, immune classical and inflammatory stroma, differ in oncogenic pathways and extent of desmoplasia. Analysis of cell-cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class has the lowest immune infiltration with abundant regulatory T cells, while the hepatic stem-like class is enriched in 'M2-like' macrophages and specific mutations. Comparative analysis reveals high similarity between a KRAS/p19 murine model and the inflammatory stroma class. The KRAS-SOS inhibitor sensitizes a KRAS-mutant iCCA murine model to anti-PD1 therapy. Our findings provide valuable insights into the TME of iCCA and offer potential therapeutic targets for future research.

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Article Medicine, General & Internal

Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma

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Summary: In this study, 103 patients with FGFR2-altered intrahepatic cholangiocarcinoma were treated with futibatinib for a median duration of 17.1 months. The results showed that futibatinib treatment could effectively inhibit tumor growth, improve survival, and maintain quality of life for patients.

NEW ENGLAND JOURNAL OF MEDICINE (2023)

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Summary: Mutations in IDH1, IDH2, and TET2 genes are commonly observed in myeloid neoplasms. These mutations have unexpected, distinct effects on hematopoietic stem and progenitor cells, contrary to previous expectations. Understanding these molecular alterations could lead to the development of more effective, genotype-specific therapies.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2023)

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Article Oncology

Effi cacy of a Small-Molecule Inhibitor of Kras G12D in Immunocompetent Models of Pancreatic Cancer

Samantha B. Kemp et al.

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Tatsuya Ioka et al.

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Rational development of combination therapies for biliary tract cancers

James J. Harding et al.

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Summary: FGF/FGFR signaling is important in cell fate and angiogenesis, and its dysregulation can drive tumorigenesis. Combining FGFR inhibitors with immune checkpoint blockade may be a promising treatment option for patients with dysregulated FGF/FGFR signaling.

MOLECULAR CANCER (2023)

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Review Oncology

Cholangiocarcinoma - novel biological insights and therapeutic strategies

Sumera I. Ilyas et al.

Summary: Cholangiocarcinoma still has a poor prognosis and better understanding of the disease biology is needed for early detection and treatment. In the past 5 years, significant advances have been made in the scientific understanding and clinical management of cholangiocarcinoma, including insights into the tumor microenvironment, progress in liquid biopsy approaches, targeted therapies, immunotherapies, and reassessment of liver transplantation.

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Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma

Naoshi Nishida et al.

Summary: Cholangiocarcinoma (CCA) is a resistant cancer, and a majority of CCAs have a non-inflamed tumor phenotype resistant to treatment, including immune checkpoint inhibitors (ICIs). This study aimed to understand the molecular characteristics of non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was analyzed, and it was found that tumors with alterations in FGFR2 and IDH1/2 had a non-inflamed phenotype. Downregulation of genes involved in antigen presentation and DNA methylation were associated with the non-inflamed phenotype. These findings provide important insights for developing new strategies to treat CCA.

CANCERS (2023)

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Spatial immunophenotypes predict clinical outcome in intrahepatic cholangiocarcinoma

Chunbin Zhu et al.

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Cancer-Associated Fibroblasts and Extracellular Matrix: Therapeutical Strategies for Modulating the Cholangiocarcinoma Microenvironment

Mirko Minini et al.

Summary: Immunotherapy has greatly impacted anti-tumor treatments, but solid tumor treatment has fallen short of expectations. Cholangiocarcinoma (CCA) is a leading cause of hepatic cancer-related deaths due to drug inefficacy and chemo-resistance. Research is ongoing to understand the mechanisms of chemo-resistance and the role of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) and the excess production of aberrant extracellular matrix (ECM) by these cells may limit drug access and contribute to immune exclusion. This article summarizes the features, functions, and interactions of CAFs, tumor-associated ECM, and immune cells in the TME, and discusses strategies to target CAFs and remodel the ECM for improved immunotherapy and drug therapies.

CURRENT ONCOLOGY (2023)

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Inhibition of FGFR Reactivates IFNg Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies

Yusuke Adachi et al.

Summary: This study examined the antitumor activity of lenvatinib and axitinib combined with anti-PD-1 mAb in renal cell carcinoma (RCC) and found that the combination treatments showed greater antitumor activity and longer survival compared to single agent treatments. Lenvatinib specifically had enhanced antitumor activity and restored tumor response to IFNg stimulation by inhibiting FGFR signaling. These findings suggest the importance of FGFR signaling in cancer immunity and the potential of combination therapy with lenvatinib plus anti-PD-1 mAb.

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Tu-Xiong Huang et al.

Summary: Solid tumours have poor response to ICI therapies due to the immunosuppressive TME, where CAFs play a key role in negatively regulating antitumor T-cell responses. Targeting WNT2 secreted by CAFs could enhance ICI efficacy and serve as a new approach for anticancer immunotherapy.

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Mutant IDH Inhibits IFNγ-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Meng-Ju Wu et al.

Summary: Mutant IDH1 (mIDH1) supports cholangiocarcinoma tumor maintenance through immunoevasion and inactivation of TET2, and pharmacologic mIDH1 inhibition stimulates immune response and TET2-dependent induction of IFNγ response genes, which can be enhanced by CTLA4 blockade.

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Article Gastroenterology & Hepatology

GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity

Luis Ruffolo et al.

Summary: Intrahepatic cholangiocarcinoma (iCCA) is characterized by infiltration of suppressive myeloid populations, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Tumors overexpress granulocyte-macrophage colony-stimulating factor (GM-CSF) which promotes an immunosuppressive microenvironment, but blocking GM-CSF shows promise in promoting anti-tumor immunity and regression.

GUT (2022)

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HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability

Masahito Kawazu et al.

Summary: This study analyzed mutations in HLA-ABC genes in colorectal cancers and found a subtype of tumors with reduced lymphocyte infiltration due to decreased expression of HLA-ABC genes. Patients with these tumors had shorter survival time, despite having a higher tumor mutation burden, suggesting a counterbalance between immunogenic effects and weakened immunoreactivity. Various genetic and epigenetic alterations led to reduced expression of HLA-ABC genes.

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Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study

Funda Meric-Bernstam et al.

Summary: Futibatinib, a selective FGFR1-4 inhibitor, showed clinical activity in various solid tumors, particularly in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. It also demonstrated efficacy in patients who developed resistance to prior FGFR inhibitors. These findings provide a basis for further clinical trials and highlight the importance of genomic profiling in identifying patients who may benefit from targeted therapy.

CANCER DISCOVERY (2022)

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Article Multidisciplinary Sciences

Single-cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma

Guohe Song et al.

Summary: This study characterizes the molecular classification and tumor microenvironment of intrahepatic cholangiocarcinoma (iCCA) using single cell RNA-sequencing. The authors identify S100P and SPP1 as markers for patient classification and demonstrate that different subtypes of iCCA have distinct immune cell infiltration and survival rates.

NATURE COMMUNICATIONS (2022)

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Article Gastroenterology & Hepatology

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study

Do-Youn Oh et al.

Summary: In patients with advanced biliary tract cancer, gemcitabine and cisplatin plus immunotherapy showed promising efficacy and acceptable safety, with an objective response rate of 66%. The most common adverse events were hematological, with no unexpected safety events observed.

LANCET GASTROENTEROLOGY & HEPATOLOGY (2022)

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Review Medicine, General & Internal

Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma

Taek Chung et al.

Summary: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with distinct histopathologic features and molecular profiles. The classification of small duct type and large duct type iCCA provides important insights into the tumor behavior and prognosis. Understanding the tumor microenvironment and genomic characteristics can help develop precision therapeutics for patients with iCCA.

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Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study

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Geospatial Immune Heterogeneity Reflects the Diverse Tumor-Immune Interactions in Intrahepatic Cholangiocarcinoma

Youpei Lin et al.

Summary: This study elucidates the impact of spatial immune heterogeneity upon tumor evolution of iCCA and reveals distinct immune evasion mechanisms developed in different immune microenvironments, which can be exploited for the development of personalized immunotherapy strategies.

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Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis

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Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing-Assisted Multiomics Analysis

Xuanwen Bao et al.

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Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures

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JCO PRECISION ONCOLOGY (2022)

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CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

Laurence P. Diggs et al.

Summary: Stimulating antigen-presenting cells such as macrophages and dendritic cells through CD40 agonist significantly enhances the response to anti-PD-1 therapy in intrahepatic cholangiocarcinoma (iCCA) models, leading to a greater reduction in tumor burden. The combination of CD40 agonist and PD-1 inhibitor, along with chemotherapy, shows promising results in improving therapeutic efficacy and overall survival.

JOURNAL OF HEPATOLOGY (2021)

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Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study

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Anti-PD-1 in Combination With Trametinib Suppresses Tumor Growth and Improves Survival of Intrahepatic Cholangiocarcinoma in Mice

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