机构：[1]Edwin. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA. [2]Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China. [3]Immuno-oncology Research and Development, Sanofi, Cambridge, USA. [4]Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 中山大学附属第一医院[5]Department of Surgery, Tohoku Graduate School of Medicine, Sendai, Japan. [6]Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, USA. [7]Kanazawa University Institute of Medical, Pharmaceutical and Health Sciences Faculty of Medicine, Kanazawa, Japan. [8]Xiangya Hospital, Central South University, Changsha, China. [9]Center of Computational and Integrative Biology (CCIB), Massachusetts General Hospital and Harvard Medical School, Boston, USA. [10]Department of Aerospace and Mechanical Engineering, College of Engineering, University of Notre Dame, Notre Dame, USA. [11]West China Hospital of Sichuan University, Chengdu, China. 四川大学华西医院[12]Jiaotong University, Xi’an, China. [13]Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA. [14]Department of Orthopedics, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the PD1 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-CTLA-4 when combined with anti-PD1 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/PD1 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 since 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-PD1 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.
基金：
National Institutes of Health grants
R01CA260857, R01CA254351, R03CA256764, and P01CA261669 (DGD), National
Institutes of Health grant R01CA247441 (LLM, DGD), Department of Defense PRCRP
grants W81XWH-19-1-0284 and W81XWH-21-1-0738 (DGD), National Institutes of Health
grant K22CA258410 (MD), National Institutes of Health grant P30CA006973 (WJH),
National Institutes of Health grant U01CA224348, R01CA259253, R01CA208205,R01NS118929, U01CA261842 (RKJ), and Cholangiocarcinoma Research Foundation postdoctoral fellowship (SA)
第一作者机构：[1]Edwin. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA. [2]Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Chen Jiang,Amoozgar Zohreh,Liu Xin,et al.Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy[J].CANCER IMMUNOLOGY RESEARCH.2024,12(4):400-412.doi:10.1158/2326-6066.CIR-23-0486.
APA：
Chen Jiang,Amoozgar Zohreh,Liu Xin,Aoki Shuichi,Liu Zelong...&Duda Dan G.(2024).Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy.CANCER IMMUNOLOGY RESEARCH,12,(4)
MLA：
Chen Jiang,et al."Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy".CANCER IMMUNOLOGY RESEARCH 12..4(2024):400-412
医学