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CAR structures of CAR-T and CAR-macrophage.CAR-T cells have undergone four generations of development (top panel), with each generation possessing distinct cytoplasmic domains. The first-generation CAR-T cells only express CD3ζ as their cytoplasmic signaling domain. The second-generation CAR-T cells incorporate a costimulatory domain, such as CD28 or 4-1BB, to provide a second signal for T cell activation. The third-generation CAR-T cells have two costimulatory domains. The fourth-generation CAR-T cells, in addition to CD3ζ and costimulatory domains, have a cytokine sequence downstream of CD3ζ, which enables them to produce proinflammatory cytokines (e.g., IL-7, IL-33, IL-12) upon antigen recognition. A P2A peptide is added to cleave the cytokine from the antigen receptor. The CAR design employed in CAR-macrophages comprises an antigen binding domain, a hinge region, a transmembranedomain, and a cytoplasmic signaling domain, and exhibits great diversity in their cytoplasmic signaling domains (bottom panel). The signaling domains of CD3ζ and FcRγ can mediate antigen-specific phagocytosis, while CAR-macrophages that utilize CD147 as asignaling domain can secrete matrix metalloproteinases (MMPs) to break down the dense extracellular matrix surrounding solid tumors. Additionally, in a recent study by Niu et al., CCL19, instead of single chain variable fragment (scFv), was utilized as the antigen-binding domain for CAR-macrophages to target an immunosuppressive cell population highly expressing CCR7, instead of scFv. (This figure was created at BioRender.com.)
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