Cholangiocarcinoma is characterized by a poor prognosis with limited treatment and management options. Chemotherapy using gemcitabine with cisplatin is the only available first-line therapy for patients with advanced cholangiocarcinoma, although it offers only palliation and yields a median survival of < 1 year. Recently there has been a resurgence of immunotherapy studies focusing on the ability of immunotherapy to inhibit cancer growth by impacting the tumor microenvironment. Based on the TOPAZ-1 trial, the US Food and Drug Administration has approved the combination of durvalumab and gemcitabine with cisplatin as the first-line treatment of cholangiocarcinoma. However, immunotherapy, like immune checkpoint blockade, is less effective in cholangiocarcinoma than in other types of cancer. Although several factors such as the exuberant desmoplastic reaction are responsible for cholangiocarcinoma treatment resistance, existing literature on cholangiocarcinoma cites the inflammatory and immunosuppressive environment as the most common factor. However, mechanisms activating the immunosuppressive tumor microenvironment contributing to cholangiocarcinoma drug resistance are complicated. Therefore, gaining insight into the interplay between immune cells and cholangiocarcinoma cells, as well as the natural development and evolution of the immune tumor microenvironment, would provide targets for therapeutic intervention and improve therapeutic efficacy by developing multimodal and multiagent immunotherapeutic approaches of cholangiocarcinoma to overcome the immunosuppressive tumor microenvironment. In this review, we discuss the role of the inflammatory microenvironment-cholangiocarcinoma crosstalk and reinforce the importance of inflammatory cells in the tumor microenvironment, thereby highlighting the explanatory and therapeutic shortcomings of immunotherapy monotherapy and proposing potentially promising combinational immunotherapeutic strategies.
Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, andin vivoT-cell depletion and CD8+T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+T-cells. Depletion of CD8+but not CD4+T-cells compromised efficacy. Conversely, CD8+T-cell transfer from Cxcr3-/-versus Cxcr3+/+mice into Rag1-/-immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 ″priming″) with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.
Co-inhibition of programmed cell death receptor-1 (PD-1) and vascular endothelial growth factor receptor (VEGFR) pathway has shown efficacy in hepatocellular carcinoma (HCC). NLRP3 is a component of the inflammasome involved in the initiation, development, and progression of multiple cancers. We examined whether adding an NLRP3 agonist to dual PD-1/VEGFR inhibitors is feasible and can address treatment resistance in orthotopic HCC in mice with underlying liver damage. Mice with established tumors were treated with an NLRP3 agonist alone, combination of anti-VEGFR2 or the multikinase inhibitor regorafenib with anti-PD1 antibodies, or their combination. In all models tested, NLRP3 agonist therapy showed acceptable toxicity but no effect on tumor growth delay, disease morbidity, or survival. Pharmacodynamic analyses confirmed the effects of NLRP3 agonist therapy on inflammasome, evidenced by a significant elevation in plasma levels of pro-inflammatory cytokines such as IL-1β. However, these changes were not detectable in tumor tissues, where we detected increased expression of immunosuppressive markers IL-6, KC/GRO, CCL9, and IL-18, and immune checkpoint molecules (PD1, PD-L1, and CTLA-4) after NLRP3 agonist therapy. Thus, modulation of the inflammasome with a novel NLRP3 agonist was feasible in mice with orthotopic HCC and liver damage but did not enhance efficacy when combined with anti-PD1/VEGFR therapies.
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