Figure 2.

Novel immunotherapeutic approaches for the treatment of advanced CCA. (A) Bispecific antibodies have two binding domains that can bind to two different antigens or epitopes simultaneously. (B) Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-β receptor II, a so-called trap, fused to a human IgG1 anti-PD-L1 antibody. The trap binds to TGF-β, therefore blocking all the downstream pathways that promote immunosuppression, epithelial-mesenchymal transition of tumor cells, fibrosis and proliferation of cancer-associated fibroblasts, and neo-angiogenesis. Simultaneously, the interaction between the anti-PD-L1 domain and the PD-L1 expressed on tumor cells promotes the activation of an immune response. (C) mRNA encoding tumor antigens are delivered as vaccines. The mRNA is taken up by dendritic cells, translated into the correspondent tumor antigen, then presented to T lymphocytes, thus inducing an immune response. (D) Adoptive cell therapy refers to two different approaches: TILs and CAR-T cells. TILs are extracted from the tumor microenvironment, expanded in vitro with IL-2 and feeder cells, then re-administered to the patient. They can induce a cell-mediated immune reaction against cancer cells. CAR-Ts are T lymphocytes derived from the patient and engineered to express receptors that target specific tumor antigens. (E) Cytokines act as immunostimulatory agents, that promote the activation of DCs, NKs, and macrophages. Created with BioRender.com. DC, dendritic cell; NK, natural killer lymphocyte; TIL, tumor infiltrating lymphocytes; CAR-T, chimeric antigen receptor T; TC, tumor cell; TIGIT, T cell immunoreceptor with Ig and ITIM domains; PD-1, programmed death 1; CTLA-4, cytotoxic T-lymphocyte antigen 4; mRNA, messenger ribonucleic acid; MHC, major histocompatibility complex; PD-L1, programmed death ligand 1; TGF- β, transforming growth factor β; CCA, cholangiocarcinoma; Ig, immunoglobulin; ITIM, immunoreceptor tyrosine-based inhibitory motif.