ArticleCancer immunology research2024
Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.
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Article in Cancer immunology research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24citing papers in PubMed
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24 citing papers in PubMed, 24 citations in OpenAlex.
- ATP7A-mediated copper ion efflux reprogrammes tumour immunity and promotes cisplatin resistance in cervical cancer.Cell death & disease · 2026Article
- Role of the stromal and immune microenvironment in intrahepatic cholangiocarcinoma.JHEP reports : innovation in hepatology · 2026Review
- Review
- Safety and efficacy of PD-1/PD-L1 inhibitors combined with albumin-bound paclitaxel and fluorouracil-based agents as second-line therapy in biliary tract cancers.World journal of surgical oncology · 2026Article
- A case of perihilar cholangiocarcinoma with peritoneal dissemination that achieved a pathological complete response using immune checkpoint inhibitors: A case report.International cancer conference journal · 2026Article
- Cancer and aging: complex associations and therapeutic targets.Molecular biomedicine · 2026Review
- Tertiary lymphoid structure topotypes in intrahepatic cholangiocarcinoma: spatial immunity, checkpoint-response associations, and therapeutic reprogramming.Frontiers in immunology · 2026Review
- Stratifying cholangiocarcinoma: tumor microenvironment, molecular drivers, and novel immunotherapeutic approaches.Clinical and molecular hepatology · 2026Review
- Surgery vs. non-surgery for advanced cholangiocarcinoma post-conversion therapy with PD-1/PD-L1 inhibitors plus TKIs.Frontiers in immunology · 2026Article
- Inhibiting B cells enhances the efficacy of STING agonism or immune checkpoint blockade in hepatocellular carcinoma.Nature communications · 2025Article
- The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: a new approach to enhance anti-tumor efficacy.Annals of medicine · 2025Review
- Research progress on immune checkpoint inhibitors in intrahepatic cholangiocarcinoma.Annals of medicine · 2025Review
- Single-cell multi-omics in biliary tract cancers: decoding heterogeneity, microenvironment, and treatment strategies.Molecular biomedicine · 2025Review
- Mitochondria-targeting polymer cLipG/CuET activates the cGAS/STING pathway to enhance cholangiocarcinoma immunotherapy.Journal of nanobiotechnology · 2025Article
- Article
- Identification of biomarkers associated with exhausted CD8 + T cells in the tumor microenvironment of intrahepatic cholangiocarcinoma based on Mendelian randomization and bioinformatics analysis.Discover oncology · 2025Article
- Ligustilide Inhibits the PI3K/AKT Signalling Pathway and Suppresses Cholangiocarcinoma Cell Proliferation, Migration, and Invasion.Recent patents on anti-cancer drug discovery · 2025Article
- Advancing biliary tract malignancy treatment: emerging frontiers in cell-based therapies.Frontiers in immunology · 2025Review
- Chemokines: humble yet mighty players in the tumour microenvironment.Frontiers in immunology · 2025Review
- New dimensions of PD-1/PD-L1 inhibitor combination therapy in cancer treatment: current advances and future perspectives.Frontiers in immunology · 2025Review
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Authors and funding
25 authors at 12 institutions in 3 countries.
Jiang Chen *Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-7414-8575
Zohreh Amoozgar *Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-8285-8024
Xin Liu *Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-7529-3149
Shuichi AokiEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-4221-0236
Zelong LiuEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-6643-7772
Sarah M ShinSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.ORCID 0000-0002-7658-5899
Aya MatsuiEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-4903-3511
Alexei HernandezSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.ORCID 0000-0002-6044-2631
Zhangya PuEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-5721-3512
Stefan HalvorsenCenter of Computational and Integrative Biology (CCIB), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-8150-6780
Pin-Ji LeiEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-2539-5179
Meenal DattaEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-5727-8992
Lingling ZhuEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-1794-3147
Zhiping RuanEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-9467-7466
Lei ShiDepartment of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-1149-0474
Daniel StaiculescuEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-6064-9328
Koetsu InoueEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0009-0000-9009-3084
Lance L MunnEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-0698-7232
Dai FukumuraEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-9505-4444
Peigen HuangEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-3184-6493
Slim SassiCenter of Computational and Integrative Biology (CCIB), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-6329-4980
Nabeel BardeesyDepartment of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-3867-0416
Won Jin HoSidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.ORCID 0000-0003-2644-5086
Rakesh K JainEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-7571-3548
Dan G DudaEdwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-7065-8797
Massachusetts General Hospital · USHarvard University · USJohns Hopkins University · USSun Yat-sen University · CNTohoku University · JPAVEO Oncology (United States) · USCentral South University · CNKanazawa University · JPSichuan University · CNSir Run Run Shaw Hospital · CNTongji University · CNUniversity of Notre Dame · US
Funding
Translational Research Central ServicesP30CA006973 · NCI · JOHNS HOPKINS UNIVERSITY · PI WILLIAM George NELSON · 1985 to 2026
$208.6MTissue and Pathology ResourcesP50CA127003 · NCI · DANA-FARBER CANCER INST · PI BASS, ADAM JOEL · 2007 to 2023
$33.2MProject 3: Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers.P01CA261669 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI GROSSHANS, DAVID R · 2021 to 2025
$14.0MTargeting physical stress-driven mechanisms to overcome glioblastoma treatment resistanceU01CA261842 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K., MUNN, LANCE L. · 2021 to 2025
$3.1MReprogramming PDAC tumor microenvironment to improve immunotherapyU01CA224348 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI BOUCHER, YVES, JAIN, RAKESH K. · 2017 to 2021
$2.9MMultiplexed time domain fluorescence tomography of tumor biomarkers during immunotherapyR01CA260857 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Dan Gabriel Duda, Anand T.N. Kumar · 2021 to 2026
$2.7M(PQ7) In Vivo Cellular Optical Imaging of Esophageal Tumors and MicroenvironmentR01CA205431 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI PERELMAN, LEV T · 2016 to 2020
$2.6MImproving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolismR01CA259253 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K., VANDER HEIDEN, MATTHEW G. · 2021 to 2025
$2.3MReengineering obesity-induced abnormal microenvironment to improve PDAC treatmentR01CA208205 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI, JAIN, RAKESH K. · 2017 to 2020
$2.2MReprogramming the Tumor Microenvironment to Improve Immunotherapy of Glioblastoma by Co-Targeting VEGF and Ang2R01NS118929 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI · 2021 to 2025
$2.0MReprogramming the tumormicroenvironment to improve immunotherapy of glioblastomaR01CA269672 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Rakesh K. Jain · 2022 to 2026
$1.9MVascularized tumor explants for drug testingR01CA247441 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI MUNN, LANCE L. · 2021 to 2025
$1.9MNCI NIH HHS K22 CA258410NCI NIH HHS P01 CA261669NCI NIH HHS P30 CA006973NCI NIH HHS P50 CA127003NCI NIH HHS R01 CA205431NCI NIH HHS R01 CA208205NCI NIH HHS R01 CA247441NCI NIH HHS R01 CA259253NCI NIH HHS R01 CA260857NCI NIH HHS R01 CA269672NCI NIH HHS R03 CA256764NCI NIH HHS U01 CA224348NCI NIH HHS U01 CA261842NIGMS NIH HHS R35 GM151041NINDS NIH HHS R01 NS118929
Abstract
Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.
Indexed as
CholangiocarcinomaCisplatinGemcitabineAnimalsCD8-Positive T-LymphocytesCTLA-4 AntigenHumansMiceTumor MicroenvironmentCisplatinCTLA-4 AntigenGemcitabine
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