Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti–PD-1 Therapy

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 CD8þCxcr3þIFNgþ T cells. CD8þ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8þ T cells were depleted. Expression of Cxcr3 on CD8þ T cells is necessary and sufficient because CD8þ T cells from Cxcr3þ/þ 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.