Understanding the Spatial Topology of Artificial Immunological Synapses Assembled in T Cell-Redirecting Strategies: A Major Issue in Cancer Immunotherapy

摘要

T cell-redirection strategies aim to selectively eliminate cancer cells by physically linking Tlymphocytes with cancer cells using tumor-targeted cell-cell bridging (CCB) molecules, such asmembrane-anchored chimeric antigen receptors (CARs) or soluble bispecific antibodies (bsAbs)that specifically recognize a cell-surface tumor-associated antigen (TAA) (Blanco et al., 2019).In the CAR approach, a TAA-specific antibody is genetically fused to intracellular T cellsignaling domains. CARs have evolved greatly since their initial description, as single-chainantibody fragment (scFv)-based receptors containing the signaling domain of the CD3ζ chain(CD247) of the T cell receptor (TCR) (Eshhar et al., 1993). Subsequently, constructs incorporatingsignaling domains of costimulatory molecules (e.g., CD28 or 4-1BB) in tandem with the CD3ζsignaling domain were generated (Finney et al., 1998). Engrafting T-cells with such receptors,termed second-generation CARs, enables sustained proliferation and increased cytokine secretion.Third-generation CARs contain two costimulatory domains, in addition to the CD3ζ signalingdomain (Carpenito et al., 2009; Milone et al., 2009). Current CAR-T cell therapy involves theisolation of autologous T cells using leukapheresis, followed by in vitro stimulation, geneticmodification to express the TAA-specific CAR, and expansion to infuse back into the patient(Blanco et al., 2019). The bsAbs are designed to simultaneously bind to the TAA in the surfaceof tumor cells and the CD3ε chain of the TCR/CD3 complex in the surface of T cells (Blanco et al.,2019). More than a 100 different bsAb formats have been reported, including small bsAbs composedonly by two antigen-binding sites, IgG-like bsAbs and larger and non-IgG bsAbs formed bydifferent antigen-binding moieties, often combined with oligomerization modules (Nu?ez-Pradoet al., 2015; Brinkmann and Kontermann, 2017). By connecting CD3 signaling molecules with arecognition process independent of the TCR variable domains, T cells can be hot-wired to recognizea user-defined cell-surface TAA that is not associated with the major histocompatibility complex(MHC) to activate effector cell responses and kill cancer cells (Blanco et al., 2019). Nonetheless,the precise molecular mechanisms by which T cells are activated through these CCB molecules arepoorly understood.