Several immune checkpoint blockades (ICBs) capable of overcoming the immunosuppressive roles of the tumor immune microenvironment have been approved by the US Food and Drug Administration as front-line treatments of various tumor types. However, due to the considerable heterogeneity of solid tumor cells, inhibiting one target will only influence a portion of the tumor cells. One way to enhance the tumor-killing efficiency is to develop a multiagent therapeutic strategy targeting different aspects of tumor biology and the microenvironment to provide the maximal clinical benefit for patients with late-stage disease. One such strategy is the administration of anti-PD1, an ICB, in combination with the humanized monoclonal antibody bevacizumab, an anti-angiogenic therapy, to patients with recurrent/metastatic malignancies, including hepatocellular carcinoma, metastatic renal cell carcinoma, non-small cell lung cancer, and uterine cancer. Radiotherapy (RT), a critical component of solid cancer management, has the capacity to prime the immune system for an adaptive antitumor response. Here, we present an overview of the most recent published data in preclinical and clinical studies elucidating that RT could further potentiate the antitumor effects of immune checkpoint and angiogenesis dual blockade. In addition, we explore opportunities of triple combinational treatment, as well as discuss the challenges of validating biomarkers and the management of associated toxicity.
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.
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